{ "$schema_version": "5.3", "review_mode": "fresh", "claim_restatement": { "index_wording": "Excitotoxicity Hypothesis", "entry_form": "phenomenon", "gradeable_restatement": "Excitotoxicity—excess glutamatergic signaling from impaired astrocytic EAAT2/GLT-1 clearance and calcium-permeable AMPA receptors—is the causal driver of motor-neuron death in ALS.", "restatement_required": true, "split_into": [], "parent_claim": null, "scope_qualifiers": [ { "qualifier": "Genotype, motor pool, disease stage, endogenous lesion versus transgene background, drug dose and neuronal versus functional endpoint", "determinable_before_outcome": true, "determined_from": "Enrollment and experimental design, before results; no responder-defined scope.", "action": "retained" } ] }, "hypothesis": { "name": "Excitotoxicity Hypothesis", "central_claim": "Excitotoxicity—excess glutamatergic signaling from impaired astrocytic EAAT2/GLT-1 clearance and calcium-permeable AMPA receptors—is the causal driver of motor-neuron death in ALS.", "proposed_mechanism": "Excitotoxicity—excess glutamatergic signaling from impaired astrocytic EAAT2/GLT-1 clearance and calcium-permeable AMPA receptors—is the causal driver of motor-neuron death in ALS.", "claimed_scope": "ALS motor-neuron death and progression, with forced-lesion and SOD1 subclaims kept distinct from sporadic-human primacy.", "claimed_level": [ "progression", "selective vulnerability" ], "is_conjunctive": true, "conjunctive_note": "Use index ALS progression scope rather than merge acute stroke and chronic neurodegeneration. Separate forced ADAR2/GLT-1 lesions, SOD1-specific rescue, broad sporadic primacy and generalization. SC4 gates the nominal causal-driver inference; stronger bounded results are visible separately." }, "rubric_routing": { "primary_rubric": "01-neurodegeneration.md", "secondary_rubrics": [], "index_notes_applied": [ "Use index ALS progression scope rather than merge acute stroke and chronic neurodegeneration. Separate forced ADAR2/GLT-1 lesions, SOD1-specific rescue, broad sporadic primacy and generalization. SC4 gates the nominal causal-driver inference; stronger bounded results are visible separately." ], "rubric_fit_note": "Exact archived v5.3 framework. Any stale index empirical framing is rechecked against primary results." }, "subclaim_matrix": { "subclaims": [ { "id": "SC1", "statement": "Excitotoxic signatures are present in ALS tissue.", "subclaim_type": "existence", "scope": "prespecified ALS cohorts and cell populations", "claimed_scope": "prespecified ALS cohorts and cell populations", "governing_rubric": "01-neurodegeneration.md", "key_evidence_anchor": "EAAT2, GluA2 editing and glutamate measurements", "hsef_level": "Β", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Β: selective transporter loss, editing defects and excitability patterns are reproducible but spatial/postmortem associations cannot determine disease dependency." }, { "id": "SC2", "statement": "Forced loss of endogenous ADAR2 or GLT-1 machinery kills motor neurons in vivo.", "subclaim_type": "sufficiency", "scope": "defined cell-specific genetic lesions", "claimed_scope": "defined cell-specific genetic lesions", "governing_rubric": "01-neurodegeneration.md", "key_evidence_anchor": "Endogenous conditional loss and matched rescue", "hsef_level": "Ζ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Ζ: distinct endogenous ADAR2 and spinal GLT1 lesions produce motor phenotypes; endogenous edited-GluR2 rescue in AR2 narrows the major ADAR2 off-target alternative. Membralin/EAAT2 rescue adds a different glial pathway. This scope is forced-lesion sufficiency, not spontaneous disease primacy." }, { "id": "SC3", "statement": "Preventing caspase-3 cleavage of EAAT2 slows functional decline in SOD1-G93A mice.", "subclaim_type": "necessity", "scope": "D505N EAAT2 and SOD1-G93A settings", "claimed_scope": "D505N EAAT2 and SOD1-G93A settings", "governing_rubric": "01-neurodegeneration.md", "key_evidence_anchor": "Endogenous knock-in functional and survival contrasts", "hsef_level": "Ε", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Ε: endogenous caspase-resistant EAAT2 knock-in changes functional progression and survival in the defined SOD1-G93A context. Transport kinetics and transgene-copy controls strengthen attribution, while absent onset/neuron-count effects and toxic-fragment mechanisms restrict the causal claim." }, { "id": "SC4", "statement": "Excitotoxicity is the primary obligate driver of motor-neuron loss in sporadic human ALS.", "subclaim_type": "primacy", "scope": "prospectively defined sporadic ALS and stage", "claimed_scope": "prospectively defined sporadic ALS and stage", "governing_rubric": "01-neurodegeneration.md", "key_evidence_anchor": "Selective receptor/clearance correction with survival and causal ordering", "hsef_level": "Γ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Γ: human tissue and physiology plus model causality make the proposed obligate driver plausible, but no selective correction demonstrates sporadic-human disease dependency; clinical null/harm and stage-dependent protective excitation remain material separators." }, { "id": "SC5", "statement": "SOD1 and ADAR2-null mechanisms generalize across sporadic ALS.", "subclaim_type": "generalization", "scope": "genotype, stage and disease classes defined before outcome", "claimed_scope": "genotype, stage and disease classes defined before outcome", "governing_rubric": "01-neurodegeneration.md", "key_evidence_anchor": "Cross-system causal confirmation and human clinical tests", "hsef_level": "Γ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Γ: familial/cell-specific models and human-associated signatures do not converge on universal progression dependence. Riluzole benefit is real but multi-action; perampanel and ceftriaxone do not supply the missing selective clinical test." } ], "aggregation_rule": "scope-matched", "aggregation_preregistered": true, "aggregation_rationale": "Use index ALS progression scope rather than merge acute stroke and chronic neurodegeneration. Separate forced ADAR2/GLT-1 lesions, SOD1-specific rescue, broad sporadic primacy and generalization. SC4 gates the nominal causal-driver inference; stronger bounded results are visible separately.", "primary_subclaim_id": "SC4", "aggregation_derivation": "Preregistered scope-matched SC4 returns Γ. SC2 Ζ is a bounded forced-lesion result, and SC3 Ε is a SOD1 progression result. Weakest-link sensitivity is Β from descriptive SC1, so that aggregation would mix association depth with a distinct causal-driver question.", "aggregation_alternatives": { "weakest_link_would_return": "Β", "primary_subclaim_would_return": "Γ", "scope_matched_would_return": "Γ", "note": "Separate narrow successes do not replace the preregistered gate." }, "index_rule_deviation": "" }, "competing_models": { "models_evaluated": [ { "rank_in_tournament": 1, "model_id": "M2", "is_nominal": false, "name": "TDP-43/RBP proteostasis failure", "core_claim": "RNA processing and axonal-support defects can precede or recruit excitotoxic stress.", "explains_what_nominal_does_not": "RNA processing and axonal-support defects can precede or recruit excitotoxic stress.", "strongest_supporting_evidence": [ "Functional UNC13A/STMN2 genetic links and rescue: PMID35197626,35197628,36927019." ], "strongest_contradictory_evidence": [ "Does not establish one universal primacy route; excitotoxic edited-GluA2 rescue remains strong in AR2." ], "hsef_level_for_this_model": "Ε", "rationale": "Functional UNC13A/STMN2 genetic links and rescue: PMID35197626,35197628,36927019. Does not establish one universal primacy route; excitotoxic edited-GluA2 rescue remains strong in AR2." }, { "rank_in_tournament": 2, "model_id": "M1", "is_nominal": true, "name": "Excitotoxicity", "core_claim": "Excess glutamate/calcium stress amplifies motor-neuron injury.", "explains_what_nominal_does_not": "Excess glutamate/calcium stress amplifies motor-neuron injury.", "strongest_supporting_evidence": [ "ADAR2 edited-receptor rescue and EAAT2 cleavage-resistant SOD1 progression benefit: PMID20826656,28342750." ], "strongest_contradictory_evidence": [ "Human clinical specificity is lacking; excitation can protect some presymptomatic motor pools: PMID24094105,32484501." ], "hsef_level_for_this_model": "Γ", "rationale": "ADAR2 edited-receptor rescue and EAAT2 cleavage-resistant SOD1 progression benefit: PMID20826656,28342750. Human clinical specificity is lacking; excitation can protect some presymptomatic motor pools: PMID24094105,32484501." }, { "rank_in_tournament": 3, "model_id": "M3", "is_nominal": false, "name": "Distal axonopathy/dying-back", "core_claim": "Axonal support/destruction can drive distal loss before cell bodies fail.", "explains_what_nominal_does_not": "Axonal support/destruction can drive distal loss before cell bodies fail.", "strongest_supporting_evidence": [ "Temporal NMJ loss, Stmn2 lesion/rescue and Sarm1 attenuation: PMID14736504,35294901,31661035." ], "strongest_contradictory_evidence": [ "Axonal chronology alone cannot exclude a glutamate upstream trigger; behavior does not invariably improve." ], "hsef_level_for_this_model": "Ε", "rationale": "Temporal NMJ loss, Stmn2 lesion/rescue and Sarm1 attenuation: PMID14736504,35294901,31661035. Axonal chronology alone cannot exclude a glutamate upstream trigger; behavior does not invariably improve." }, { "rank_in_tournament": 4, "model_id": "M4", "is_nominal": false, "name": "Astroglial toxicity beyond glutamate", "core_claim": "Inflammatory and metabolic glial changes interact with neurons.", "explains_what_nominal_does_not": "Inflammatory and metabolic glial changes interact with neurons.", "strongest_supporting_evidence": [ "RIPK1 perturbation, TNF-conditioned-medium blockade and MCT1 loss: PMID40132594,29380416,22801498." ], "strongest_contradictory_evidence": [ "Different systems and broader perturbations do not prove a common primary glial insult." ], "hsef_level_for_this_model": "Ε", "rationale": "RIPK1 perturbation, TNF-conditioned-medium blockade and MCT1 loss: PMID40132594,29380416,22801498. Different systems and broader perturbations do not prove a common primary glial insult." }, { "rank_in_tournament": 5, "model_id": "M5", "is_nominal": false, "name": "Homeostatic excitability compensation", "core_claim": "Excitation can recruit protective signaling in vulnerable motor neurons.", "explains_what_nominal_does_not": "Excitation can recruit protective signaling in vulnerable motor neurons.", "strongest_supporting_evidence": [ "Opposite-direction SOD1 activity/mTOR and synaptic rescue: PMID24094105,32484501." ], "strongest_contradictory_evidence": [ "Circuit, stage and genotype boundaries preclude treating all hyperexcitability as protective." ], "hsef_level_for_this_model": "Ε", "rationale": "Opposite-direction SOD1 activity/mTOR and synaptic rescue: PMID24094105,32484501. Circuit, stage and genotype boundaries preclude treating all hyperexcitability as protective." } ], "tournament_summary": "Descriptive comparison; does not modify the nominal score. A stage-matched comparison of selective receptor/clearance correction versus RNA/axonal correction, with mediator engagement and neuron/axon/function endpoints, separates an obligate glutamate pathway from parallel amplification.", "study_separating_rank1_from_rank2": "A stage-matched comparison of selective receptor/clearance correction versus RNA/axonal correction, with mediator engagement and neuron/axon/function endpoints, separates an obligate glutamate pathway from parallel amplification.", "nominal_wins_only_by_funding_artifact": false, "level_unchanged_by_tournament": true }, "evidence_inventory": [ { "n": 1, "pmid": "31112137", "title": "Membralin deficiency dysregulates astrocytic glutamate homeostasis leading to ALS-like impairment.", "citation": "Jiang LL, Zhu B, Zhao Y et al. Membralin deficiency dysregulates astrocytic glutamate homeostasis leading to ALS-like impairment. The Journal of clinical investigation. 2019.", "doi": "10.1172/JCI127695", "pmcid": "PMC6668683", "url": "https://pubmed.ncbi.nlm.nih.gov/31112137/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31112137/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID31112137", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal engineered", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Astrocytic membralin loss lowers EAAT2 and causes motor phenotypes; restoring EAAT2 or membralin protects in engineered settings.", "what_it_does_not_show": "Membralin regulates broader inflammatory pathways; forced deletion and SOD1 rescue do not establish sporadic human primacy.", "confounders_present": [ "Membralin regulates broader inflammatory pathways; forced deletion and SOD1 rescue do not establish sporadic human primacy." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 2, "pmid": "24569372", "title": "Small-molecule activator of glutamate transporter EAAT2 translation provides neuroprotection.", "citation": "Kong Q, Chang LC, Takahashi K et al. Small-molecule activator of glutamate transporter EAAT2 translation provides neuroprotection. The Journal of clinical investigation. 2014.", "doi": "10.1172/JCI66163", "pmcid": "PMC3938250", "url": "https://pubmed.ncbi.nlm.nih.gov/24569372/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24569372/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID24569372", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal engineered", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "EAAT2 translational activator improves motor function and survival in a mouse ALS model.", "what_it_does_not_show": "PKC/YB1 effects and engineered background constrain attribution; clinical spinal engagement is untested.", "confounders_present": [ "PKC/YB1 effects and engineered background constrain attribution; clinical spinal engagement is untested." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 3, "pmid": "14561930", "title": "Cells over-expressing EAAT2 protect motoneurons from excitotoxic death in vitro.", "citation": "Wisman LA, van Muiswinkel FL, de Graan PN et al. Cells over-expressing EAAT2 protect motoneurons from excitotoxic death in vitro. Neuroreport. 2003.", "doi": "10.1097/00001756-200310270-00017", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/14561930/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/14561930/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID14561930", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Weak", "system": "in vitro", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "EAAT2 overexpression protects cocultured motor neurons from glutamate exposure.", "what_it_does_not_show": "Forced receptor milieu and transporter expression do not establish endogenous ALS necessity.", "confounders_present": [ "Forced receptor milieu and transporter expression do not establish endogenous ALS necessity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 4, "pmid": "11031254", "title": "Amyotrophic lateral sclerosis-linked glutamate transporter mutant has impaired glutamate clearance capacity.", "citation": "Trotti D, Aoki M, Pasinelli P et al. Amyotrophic lateral sclerosis-linked glutamate transporter mutant has impaired glutamate clearance capacity. The Journal of biological chemistry. 2001.", "doi": "10.1074/jbc.M003779200", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/11031254/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/11031254/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID11031254", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Weak", "system": "human ex vivo", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "An EAAT2 N206S variant detected in an ALS patient impairs transport-related properties in assays.", "what_it_does_not_show": "A single detected variant is not segregation evidence or an explanation of common sporadic ALS.", "confounders_present": [ "A single detected variant is not segregation evidence or an explanation of common sporadic ALS." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 5, "pmid": "40860154", "title": "An unrecognized mechanism of self-protection in degenerating neurons mediated by astrocytic YAP through Wnts/β-catenin/EAAT2 signaling in C9orf72-poly-GA mice.", "citation": "Li D, Wei Y, Yang R et al. An unrecognized mechanism of self-protection in degenerating neurons mediated by astrocytic YAP through Wnts/β-catenin/EAAT2 signaling in C9orf72-poly-GA mice. Theranostics. 2025.", "doi": "10.7150/thno.113599", "pmcid": "PMC12374586", "url": "https://pubmed.ncbi.nlm.nih.gov/40860154/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40860154/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID40860154", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 2:Results:paragraph0, 2:Results:paragraph2, 2:Results:paragraph8, 2:Results:paragraph9, 2:Results:paragraph13, 2:Results:paragraph14, 2:Results:paragraph15. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal engineered", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Astrocytic YAP loss exacerbates poly-GA-model phenotypes; LDN-212320 restores EAAT2 and partially rescues motor and neuronal readouts.", "what_it_does_not_show": "Neonatal AAV-GA100 forces the disease insult; YAP has broad effects and neuronal Wnt induction is a protective response. This is not upstream sporadic primacy.", "confounders_present": [ "Neonatal AAV-GA100 forces the disease insult; YAP has broad effects and neuronal Wnt induction is a protective response. This is not upstream sporadic primacy." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 6, "pmid": "15869527", "title": "Over-expression of the human EAAT2 glutamate transporter within neurons of mouse organotypic hippocampal slice cultures leads to increased vulnerability of CA1 pyramidal cells.", "citation": "Selkirk JV, Stiefel TH, Stone IM et al. Over-expression of the human EAAT2 glutamate transporter within neurons of mouse organotypic hippocampal slice cultures leads to increased vulnerability of CA1 pyramidal cells. The European journal of neuroscience. 2005.", "doi": "10.1111/j.1460-9568.2005.04059.x", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/15869527/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/15869527/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID15869527", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Weak", "system": "non-ALS comparator", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Neuronal EAAT2 overexpression increases glutamate injury in hippocampal slice experiments.", "what_it_does_not_show": "Non-ALS cell-role comparator; does not refute appropriate astrocytic transporter restoration.", "confounders_present": [ "Non-ALS cell-role comparator; does not refute appropriate astrocytic transporter restoration." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 7, "pmid": "8619555", "title": "Glutamate transporter gene expression in amyotrophic lateral sclerosis motor cortex.", "citation": "Bristol LA, Rothstein JD et al. Glutamate transporter gene expression in amyotrophic lateral sclerosis motor cortex. Annals of neurology. 1996.", "doi": "10.1002/ana.410390519", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/8619555/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/8619555/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID8619555", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4" ], "favors_models": [], "evidence_class": "Weak", "system": "human postmortem", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "ALS specimens show marked EAAT2 protein and transport loss without corresponding mRNA changes.", "what_it_does_not_show": "Postmortem association leaves degradation, downstream damage and reverse causation unresolved.", "confounders_present": [ "Postmortem association leaves degradation, downstream damage and reverse causation unresolved." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 8, "pmid": "21769946", "title": "Motor neuron impairment mediated by a sumoylated fragment of the glial glutamate transporter EAAT2.", "citation": "Foran E, Bogush A, Goffredo M et al. Motor neuron impairment mediated by a sumoylated fragment of the glial glutamate transporter EAAT2. Glia. 2011.", "doi": "10.1002/glia.21218", "pmcid": "PMC3896305", "url": "https://pubmed.ncbi.nlm.nih.gov/21769946/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/21769946/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID21769946", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Weak", "system": "in vitro", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Forced CTE-SUMO1 expression alters astrocytes and damages cocultured motor-neuron/axon readouts.", "what_it_does_not_show": "A toxic transporter fragment may act beyond clearance; cultured fragment expression is not physiological necessity.", "confounders_present": [ "A toxic transporter fragment may act beyond clearance; cultured fragment expression is not physiological necessity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 9, "pmid": "16426705", "title": "Increased glutamine synthetase but normal EAAT2 expression in platelets of ALS patients.", "citation": "Bos IW, Hoogland G, Meine Jansen CF et al. Increased glutamine synthetase but normal EAAT2 expression in platelets of ALS patients. Neurochemistry international. 2006.", "doi": "10.1016/j.neuint.2005.09.009", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/16426705/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/16426705/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID16426705", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Weak", "system": "human peripheral comparator", "decisive_perturbation": false, "endogenous": false, "direction": "null", "what_it_shows": "Platelet EAAT2 protein and uptake are not reduced in this ALS comparison.", "what_it_does_not_show": "Peripheral platelets do not directly test spinal astrocyte transporter dysfunction.", "confounders_present": [ "Peripheral platelets do not directly test spinal astrocyte transporter dysfunction." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 10, "pmid": "16567804", "title": "Caspase-3 cleaves and inactivates the glutamate transporter EAAT2.", "citation": "Boston-Howes W, Gibb SL, Williams EO et al. Caspase-3 cleaves and inactivates the glutamate transporter EAAT2. The Journal of biological chemistry. 2006.", "doi": "10.1074/jbc.M600653200", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/16567804/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/16567804/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID16567804", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "biochemical and animal", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Caspase-3 cleaves EAAT2 and impairs transport; mutant-SOD1 contexts contain the truncated species.", "what_it_does_not_show": "Cleavage association is not proof of disease necessity; biochemical human D505 numbering must be separated from mouse D504.", "confounders_present": [ "Cleavage association is not proof of disease necessity; biochemical human D505 numbering must be separated from mouse D504." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 11, "pmid": "11357955", "title": "Intron 7 retention and exon 9 skipping EAAT2 mRNA variants are not associated with amyotrophic lateral sclerosis.", "citation": "Flowers JM, Powell JF, Leigh PN et al. Intron 7 retention and exon 9 skipping EAAT2 mRNA variants are not associated with amyotrophic lateral sclerosis. Annals of neurology. 2001.", "doi": "", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/11357955/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/11357955/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID11357955", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "human tissue and CSF", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "EAAT2 splice variants occur in ALS and non-ALS tissue; tested CSF assays did not find the proposed transcripts.", "what_it_does_not_show": "Specific splice-variant attribution fails; neither null CSF transcripts nor this finding excludes other transporter lesions.", "confounders_present": [ "Specific splice-variant attribution fails; neither null CSF transcripts nor this finding excludes other transporter lesions." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 12, "pmid": "18326497", "title": "Mechanism of ceftriaxone induction of excitatory amino acid transporter-2 expression and glutamate uptake in primary human astrocytes.", "citation": "Lee SG, Su ZZ, Emdad L et al. Mechanism of ceftriaxone induction of excitatory amino acid transporter-2 expression and glutamate uptake in primary human astrocytes. The Journal of biological chemistry. 2008.", "doi": "10.1074/jbc.M707697200", "pmcid": "PMC2442320", "url": "https://pubmed.ncbi.nlm.nih.gov/18326497/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/18326497/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID18326497", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC5" ], "favors_models": [], "evidence_class": "Weak", "system": "in vitro", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Ceftriaxone induces EAAT2 via NF-kappaB in human fetal astrocytes; RNAi removes the uptake effect.", "what_it_does_not_show": "Fetal isolated cells are not adult spinal target engagement or clinical efficacy.", "confounders_present": [ "Fetal isolated cells are not adult spinal target engagement or clinical efficacy." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 13, "pmid": "25297012", "title": "Safety and efficacy of ceftriaxone for amyotrophic lateral sclerosis: a multi-stage, randomised, double-blind, placebo-controlled trial.", "citation": "Cudkowicz ME, Titus S, Kearney M et al. Safety and efficacy of ceftriaxone for amyotrophic lateral sclerosis: a multi-stage, randomised, double-blind, placebo-controlled trial. The Lancet. Neurology. 2014.", "doi": "10.1016/S1474-4422(14)70222-4", "pmcid": "PMC4216315", "url": "https://pubmed.ncbi.nlm.nih.gov/25297012/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25297012/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID25297012", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 2:Results:paragraph0, 2:Results:paragraph1, 2:Results:paragraph4, 2:Results:paragraph5, 3:Discussion:paragraph7. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4", "SC5" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "null", "what_it_shows": "The ceftriaxone phase-3 dataset contains 513 participants (340 active and 173 placebo); functional decline and survival were not significantly improved.", "what_it_does_not_show": "CSF exposure did not establish EAAT2 activation; hepatobiliary toxicity and treatment discontinuation constrain a mechanism-level negative inference. Consensus table 1027 and narrative 514 are not the final analysis denominator.", "confounders_present": [ "CSF exposure did not establish EAAT2 activation; hepatobiliary toxicity and treatment discontinuation constrain a mechanism-level negative inference. Consensus table 1027 and narrative 514 are not the final analysis denominator." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 14, "pmid": "24115583", "title": "Rescue of amyotrophic lateral sclerosis phenotype in a mouse model by intravenous AAV9-ADAR2 delivery to motor neurons.", "citation": "Yamashita T, Chai HL, Teramoto S et al. Rescue of amyotrophic lateral sclerosis phenotype in a mouse model by intravenous AAV9-ADAR2 delivery to motor neurons. EMBO molecular medicine. 2013.", "doi": "10.1002/emmm.201302935", "pmcid": "PMC3840487", "url": "https://pubmed.ncbi.nlm.nih.gov/24115583/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24115583/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "AR2-ADAR2-platform", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal engineered", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "AAV9-ADAR2 delivery rescues motor-neuron loss, function and TDP-43 distribution in conditional ADAR2-deficient mice.", "what_it_does_not_show": "Restoring the gene deliberately deleted in AR2 is a matched model test, not intervention in spontaneous human ALS.", "confounders_present": [ "Restoring the gene deliberately deleted in AR2 is a matched model test, not intervention in spontaneous human ALS." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 15, "pmid": "27350567", "title": "The AMPA receptor antagonist perampanel robustly rescues amyotrophic lateral sclerosis (ALS) pathology in sporadic ALS model mice.", "citation": "Akamatsu M, Yamashita T, Hirose N et al. The AMPA receptor antagonist perampanel robustly rescues amyotrophic lateral sclerosis (ALS) pathology in sporadic ALS model mice. Scientific reports. 2016.", "doi": "10.1038/srep28649", "pmcid": "PMC4923865", "url": "https://pubmed.ncbi.nlm.nih.gov/27350567/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27350567/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "AR2-ADAR2-platform", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal engineered", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Perampanel protects motor and neuronal readouts in AR2 mice.", "what_it_does_not_show": "Shares the ADAR2 lesion lineage with other AR2 reports; model rescue does not establish human tolerability or benefit.", "confounders_present": [ "Shares the ADAR2 lesion lineage with other AR2 reports; model rescue does not establish human tolerability or benefit." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 16, "pmid": "34191081", "title": "Randomized phase 2 study of perampanel for sporadic amyotrophic lateral sclerosis.", "citation": "Aizawa H, Kato H, Oba K et al. Randomized phase 2 study of perampanel for sporadic amyotrophic lateral sclerosis. Journal of neurology. 2022.", "doi": "10.1007/s00415-021-10670-y", "pmcid": "PMC8782807", "url": "https://pubmed.ncbi.nlm.nih.gov/34191081/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34191081/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID34191081", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Methods:paragraph2, 1:Methods:paragraph3, 1:Methods:paragraph5, 1:Methods:paragraph8, 2:Results:paragraph0, 2:Results:paragraph6, 2:Results:paragraph8, 2:Results:paragraph27. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4", "SC5" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "contradicts", "what_it_shows": "Perampanel randomized 66 patients and analyzed 65; only 7/21 in the 8-mg group completed 48 weeks versus 18/22 placebo. Primary mixed-model ALSFRS-R change was worse at 8 mg.", "what_it_does_not_show": "Small sample, attrition and symptomatic adverse effects limit attribution to accelerated neuronal death. Table 2 CI for the -8.4 difference is -15.0 to -1.8; abstract gives a different CI. LOCF covariance sensitivity did not retain significance.", "confounders_present": [ "Small sample, attrition and symptomatic adverse effects limit attribution to accelerated neuronal death. Table 2 CI for the -8.4 difference is -15.0 to -1.8; abstract gives a different CI. LOCF covariance sensitivity did not retain significance." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 17, "pmid": "34008857", "title": "Cortical excitability threshold can be increased by the AMPA blocker Perampanel in amyotrophic lateral sclerosis.", "citation": "Oskarsson B, Mauricio EA, Shah JS et al. Cortical excitability threshold can be increased by the AMPA blocker Perampanel in amyotrophic lateral sclerosis. Muscle & nerve. 2021.", "doi": "10.1002/mus.27328", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/34008857/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34008857/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID34008857", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Single-dose perampanel changes cortical motor threshold in a small ALS experiment.", "what_it_does_not_show": "Acute cortical physiology is not motor-neuron survival or slowed decline; curtailed recruitment limits dose comparison.", "confounders_present": [ "Acute cortical physiology is not motor-neuron survival or slowed decline; curtailed recruitment limits dose comparison." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 18, "pmid": "31092554", "title": "The RNA-binding protein FUS/TLS undergoes calcium-mediated nuclear egress during excitotoxic stress and is required for GRIA2 mRNA processing.", "citation": "Tischbein M, Baron DM, Lin YC et al. The RNA-binding protein FUS/TLS undergoes calcium-mediated nuclear egress during excitotoxic stress and is required for GRIA2 mRNA processing. The Journal of biological chemistry. 2019.", "doi": "10.1074/jbc.RA118.005933", "pmcid": "PMC6664169", "url": "https://pubmed.ncbi.nlm.nih.gov/31092554/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31092554/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID31092554", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Weak", "system": "in vitro", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Glutamate exposure causes calcium-dependent FUS/TDP-43 relocalization and GRIA2-related responses.", "what_it_does_not_show": "Forced exposure permits feedback mechanisms; it does not order the initiating lesion in ALS.", "confounders_present": [ "Forced exposure permits feedback mechanisms; it does not order the initiating lesion in ALS." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 19, "pmid": "35022247", "title": "Testing of the therapeutic efficacy and safety of AMPA receptor RNA aptamers in an ALS mouse model.", "citation": "Akamatsu M, Yamashita T, Teramoto S et al. Testing of the therapeutic efficacy and safety of AMPA receptor RNA aptamers in an ALS mouse model. Life science alliance. 2022.", "doi": "10.26508/lsa.202101193", "pmcid": "PMC8761490", "url": "https://pubmed.ncbi.nlm.nih.gov/35022247/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35022247/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "AR2-ADAR2-platform", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal engineered", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "ICV AMPA aptamers improve motor and neuronal readouts in AR2 mice.", "what_it_does_not_show": "Same conditional ADAR2 platform; no independent sporadic-human causal replication.", "confounders_present": [ "Same conditional ADAR2 platform; no independent sporadic-human causal replication." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 20, "pmid": "10627588", "title": "AMPA receptor calcium permeability, GluR2 expression, and selective motoneuron vulnerability.", "citation": "Vandenberghe W, Robberecht W, Brorson JR et al. AMPA receptor calcium permeability, GluR2 expression, and selective motoneuron vulnerability. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2000.", "doi": "10.1523/JNEUROSCI.20-01-00123.2000", "pmcid": "PMC6774105", "url": "https://pubmed.ncbi.nlm.nih.gov/10627588/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/10627588/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID10627588", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "in vitro", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Rat motor and dorsal-horn cultures show comparable whole-cell AMPA calcium permeability despite different vulnerability.", "what_it_does_not_show": "Whole-cell averages do not exclude a toxic receptor subset, and developmental rat cells are not human ALS neurons.", "confounders_present": [ "Whole-cell averages do not exclude a toxic receptor subset, and developmental rat cells are not human ALS neurons." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 21, "pmid": "18279310", "title": "Altered presymptomatic AMPA and cannabinoid receptor trafficking in motor neurons of ALS model mice: implications for excitotoxicity.", "citation": "Zhao P, Ignacio S, Beattie EC et al. Altered presymptomatic AMPA and cannabinoid receptor trafficking in motor neurons of ALS model mice: implications for excitotoxicity. The European journal of neuroscience. 2008.", "doi": "10.1111/j.1460-9568.2008.06041.x", "pmcid": "PMC3991137", "url": "https://pubmed.ncbi.nlm.nih.gov/18279310/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/18279310/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID18279310", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal engineered", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "SOD1-G93A motor neurons show presymptomatic changes in synaptic GluR1/GluR2 and CB1 distribution.", "what_it_does_not_show": "Trafficking and inferred permeability are not selective receptor blockade with a disease endpoint.", "confounders_present": [ "Trafficking and inferred permeability are not selective receptor blockade with a disease endpoint." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 22, "pmid": "26723245", "title": "Phosphorylated TDP-43 becomes resistant to cleavage by calpain: A regulatory role for phosphorylation in TDP-43 pathology of ALS/FTLD.", "citation": "Yamashita T, Teramoto S, Kwak S et al. Phosphorylated TDP-43 becomes resistant to cleavage by calpain: A regulatory role for phosphorylation in TDP-43 pathology of ALS/FTLD. Neuroscience research. 2016.", "doi": "10.1016/j.neures.2015.12.006", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/26723245/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26723245/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID26723245", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Weak", "system": "biochemical", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Phosphorylated TDP-43 and calpain-generated fragments resist further cleavage.", "what_it_does_not_show": "Biochemical persistence does not establish that excitotoxic calcium flux caused the human disease.", "confounders_present": [ "Biochemical persistence does not establish that excitotoxic calcium flux caused the human disease." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 23, "pmid": "18282609", "title": "Morphological features and responses to AMPA receptor-mediated excitotoxicity of mouse motor neurons: comparison in purified, mixed anterior horn or motor neuron/glia cocultures.", "citation": "De Paola M, Diana V, Bigini P et al. Morphological features and responses to AMPA receptor-mediated excitotoxicity of mouse motor neurons: comparison in purified, mixed anterior horn or motor neuron/glia cocultures. Journal of neuroscience methods. 2008.", "doi": "10.1016/j.jneumeth.2007.12.022", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/18282609/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/18282609/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID18282609", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Weak", "system": "in vitro", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "AMPA/kainate toxicity and apoptotic responses depend on culture composition and agonist concentration.", "what_it_does_not_show": "Glial maturation and exposure alter the result; cultured toxicity cannot carry organismal primacy.", "confounders_present": [ "Glial maturation and exposure alter the result; cultured toxicity cannot carry organismal primacy." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 24, "pmid": "17093100", "title": "Amyotrophic lateral sclerosis 2-deficiency leads to neuronal degeneration in amyotrophic lateral sclerosis through altered AMPA receptor trafficking.", "citation": "Lai C, Xie C, McCormack SG et al. Amyotrophic lateral sclerosis 2-deficiency leads to neuronal degeneration in amyotrophic lateral sclerosis through altered AMPA receptor trafficking. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2006.", "doi": "10.1523/JNEUROSCI.2084-06.2006", "pmcid": "PMC2556290", "url": "https://pubmed.ncbi.nlm.nih.gov/17093100/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/17093100/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID17093100", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal and cultured ALS2", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Alsin deficiency alters GRIP1 and surface GluR2 and increases glutamate susceptibility.", "what_it_does_not_show": "Juvenile ALS2 and receptor susceptibility are a specific context, not common sporadic disease dependency.", "confounders_present": [ "Juvenile ALS2 and receptor susceptibility are a specific context, not common sporadic disease dependency." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 25, "pmid": "17804792", "title": "Astrocytes regulate GluR2 expression in motor neurons and their vulnerability to excitotoxicity.", "citation": "Van Damme P, Bogaert E, Dewil M et al. Astrocytes regulate GluR2 expression in motor neurons and their vulnerability to excitotoxicity. Proceedings of the National Academy of Sciences of the United States of America. 2007.", "doi": "10.1073/pnas.0705046104", "pmcid": "PMC1976195", "url": "https://pubmed.ncbi.nlm.nih.gov/17804792/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/17804792/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID17804792", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "in vitro and animal", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Ventral astrocytes regulate strain-dependent GluR2 and motor-neuron susceptibility; mutant SOD1 disrupts this capacity.", "what_it_does_not_show": "Rat strain and mutant-protein context restrict generalization and do not isolate a universal initiating pathway.", "confounders_present": [ "Rat strain and mutant-protein context restrict generalization and do not isolate a universal initiating pathway." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 26, "pmid": "20826656", "title": "Induced loss of ADAR2 engenders slow death of motor neurons from Q/R site-unedited GluR2.", "citation": "Hideyama T, Yamashita T, Suzuki T et al. Induced loss of ADAR2 engenders slow death of motor neurons from Q/R site-unedited GluR2. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2010.", "doi": "10.1523/JNEUROSCI.2021-10.2010", "pmcid": "PMC6633551", "url": "https://pubmed.ncbi.nlm.nih.gov/20826656/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/20826656/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "AR2-ADAR2-platform", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Publisher HTML paragraphs:paragraph15, 0:Publisher HTML paragraphs:paragraph16, 0:Publisher HTML paragraphs:paragraph25, 0:Publisher HTML paragraphs:paragraph33, 0:Publisher HTML paragraphs:paragraph41, 0:Publisher HTML paragraphs:paragraph42, 0:Publisher HTML paragraphs:paragraph43, 0:Publisher HTML paragraphs:paragraph44, 0:Publisher HTML paragraphs:paragraph45. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC5" ], "favors_models": [], "evidence_class": "Strong", "system": "animal endogenous lesion", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Conditional ADAR2 loss in a cholinergic motor-neuron subset causes slow neuronal loss; endogenous edited-GluR2 replacement preserves neurons and motor function despite ADAR2 absence.", "what_it_does_not_show": "Developmental Cre and selective lesion define the scope; oculomotor neurons resist reduced editing. Original cell counts were blinded; rescue at six months is not a clinical sporadic-ALS test.", "confounders_present": [ "Developmental Cre and selective lesion define the scope; oculomotor neurons resist reduced editing. Original cell counts were blinded; rescue at six months is not a clinical sporadic-ALS test." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 27, "pmid": "11090861", "title": "Ca(2+)-permeable AMPA receptors and selective vulnerability of motor neurons.", "citation": "Van Den Bosch L, Vandenberghe W, Klaassen H et al. Ca(2+)-permeable AMPA receptors and selective vulnerability of motor neurons. Journal of the neurological sciences. 2000.", "doi": "10.1016/s0022-510x(00)00414-7", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/11090861/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/11090861/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID11090861", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Weak", "system": "in vitro", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Kainate selectively kills calcium-permeable-AMPA-positive motor neurons; AMPA and receptor-subset blockade prevent cultured death.", "what_it_does_not_show": "Pharmacologically forced exposure is not an ALS trajectory; GluR2 immunoreactivity does not itself imply receptor impermeability.", "confounders_present": [ "Pharmacologically forced exposure is not an ALS trajectory; GluR2 immunoreactivity does not itself imply receptor impermeability." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 28, "pmid": "9266730", "title": "Calcium-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors: a molecular determinant of selective vulnerability in amyotrophic lateral sclerosis.", "citation": "Williams TL, Day NC, Ince PG et al. Calcium-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors: a molecular determinant of selective vulnerability in amyotrophic lateral sclerosis. Annals of neurology. 1997.", "doi": "10.1002/ana.410420211", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/9266730/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/9266730/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID9266730", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Weak", "system": "human normal tissue", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "In situ assays did not detect GluR2 mRNA in normal human spinal motor neurons and predict atypical receptor composition.", "what_it_does_not_show": "Detection sensitivity and inference from transcript to assembled receptor constrain the claim; normal tissue does not establish ALS mechanism.", "confounders_present": [ "Detection sensitivity and inference from transcript to assembled receptor constrain the claim; normal tissue does not establish ALS mechanism." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 29, "pmid": "11358459", "title": "GluR2 AMPA receptor subunit expression in motoneurons at low and high risk for degeneration in amyotrophic lateral sclerosis.", "citation": "Laslo P, Lipski J, Nicholson LF et al. GluR2 AMPA receptor subunit expression in motoneurons at low and high risk for degeneration in amyotrophic lateral sclerosis. Experimental neurology. 2001.", "doi": "10.1006/exnr.2001.7653", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/11358459/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/11358459/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID11358459", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "non-ALS animal comparator", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Normal rat oculomotor and hypoglossal neurons have comparable GluR2 transcript/protein despite differing disease vulnerability.", "what_it_does_not_show": "Cross-species negative comparator challenges simple expression explanations rather than all calcium-permeable-AMPA mechanisms.", "confounders_present": [ "Cross-species negative comparator challenges simple expression explanations rather than all calcium-permeable-AMPA mechanisms." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 30, "pmid": "19185395", "title": "VEGF protects motor neurons against excitotoxicity by upregulation of GluR2.", "citation": "Bogaert E, Van Damme P, Poesen K et al. VEGF protects motor neurons against excitotoxicity by upregulation of GluR2. Neurobiology of aging. 2010.", "doi": "10.1016/j.neurobiolaging.2008.12.007", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/19185395/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/19185395/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID19185395", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "in vitro and animal", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "VEGF induces GluR2 and lowers AMPA calcium permeability and vulnerability in cultured neurons; ICV treatment induces ventral-spinal expression.", "what_it_does_not_show": "VEGF has broad effects; receptor induction in vivo is not isolated ALS survival causation.", "confounders_present": [ "VEGF has broad effects; receptor induction in vivo is not isolated ALS survival causation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 31, "pmid": "18617894", "title": "Focal degeneration of astrocytes in amyotrophic lateral sclerosis.", "citation": "Rossi D, Brambilla L, Valori CF et al. Focal degeneration of astrocytes in amyotrophic lateral sclerosis. Cell death and differentiation. 2008.", "doi": "10.1038/cdd.2008.99", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/18617894/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/18617894/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID18617894", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal engineered", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Mutant-SOD1 astrocytes are mGluR5-vulnerable; in vivo mGluR5 blockade slows astrocyte damage and modestly delays disease.", "what_it_does_not_show": "Interacting astrocyte degeneration is context specific and does not prove motor-neuron AMPA primacy.", "confounders_present": [ "Interacting astrocyte degeneration is context specific and does not prove motor-neuron AMPA primacy." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 32, "pmid": "18059133", "title": "Calcium-influx increases SOD1 aggregates via nitric oxide in cultured motor neurons.", "citation": "Kim HJ, Im W, Kim S et al. Calcium-influx increases SOD1 aggregates via nitric oxide in cultured motor neurons. Experimental & molecular medicine. 2007.", "doi": "10.1038/emm.2007.63", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/18059133/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/18059133/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID18059133", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Weak", "system": "in vitro", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Calcium ionophore increases mutant-SOD1 aggregation through nitric-oxide-linked responses in a cell line.", "what_it_does_not_show": "Forced calcium loading and transfected SOD1 do not identify physiological ALS ordering.", "confounders_present": [ "Forced calcium loading and transfected SOD1 do not identify physiological ALS ordering." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 33, "pmid": "25227219", "title": "Cortical hyperexcitability precedes lower motor neuron dysfunction in ALS.", "citation": "Menon P, Kiernan MC, Vucic S et al. Cortical hyperexcitability precedes lower motor neuron dysfunction in ALS. Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology. 2015.", "doi": "10.1016/j.clinph.2014.04.023", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/25227219/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25227219/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID25227219", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human physiological", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Cortical hyperexcitability was found in 24 ALS patients despite preserved tested APB lower-motor-unit measures.", "what_it_does_not_show": "Within-patient anatomical contrast is not pre-disease longitudinal intervention; other motor pools and occult denervation remain possible.", "confounders_present": [ "Within-patient anatomical contrast is not pre-disease longitudinal intervention; other motor pools and occult denervation remain possible." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 34, "pmid": "14523070", "title": "Hyperexcitability of cultured spinal motoneurons from presymptomatic ALS mice.", "citation": "Kuo JJ, Schonewille M, Siddique T et al. Hyperexcitability of cultured spinal motoneurons from presymptomatic ALS mice. Journal of neurophysiology. 2004.", "doi": "10.1152/jn.00665.2003", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/14523070/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/14523070/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID14523070", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Weak", "system": "in vitro", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Embryonic/neonatal SOD1-G93A cultured motor neurons have greater intrinsic firing gain.", "what_it_does_not_show": "Developmental mutant overexpression and current injection are not proof of excessive synaptic glutamate in adult ALS.", "confounders_present": [ "Developmental mutant overexpression and current injection are not proof of excessive synaptic glutamate in adult ALS." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 35, "pmid": "32484501", "title": "Synaptic restoration by cAMP/PKA drives activity-dependent neuroprotection to motoneurons in ALS.", "citation": "Bączyk M, Alami NO, Delestrée N et al. Synaptic restoration by cAMP/PKA drives activity-dependent neuroprotection to motoneurons in ALS. The Journal of experimental medicine. 2020.", "doi": "10.1084/jem.20191734", "pmcid": "PMC7398175", "url": "https://pubmed.ncbi.nlm.nih.gov/32484501/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32484501/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID32484501", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal engineered", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Presymptomatic mutant-SOD1 motor-neuron excitation is reduced; independent chemogenetic signaling/activity manipulation restores synapses and improves pathological readouts.", "what_it_does_not_show": "Does not refute cortical hyperexcitability or calcium toxicity in other stages; it contradicts uniform benefit from suppressing motor-neuron excitation.", "confounders_present": [ "Does not refute cortical hyperexcitability or calcium toxicity in other stages; it contradicts uniform benefit from suppressing motor-neuron excitation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 36, "pmid": "28436181", "title": "Cortical hyperexcitability and disease spread in amyotrophic lateral sclerosis.", "citation": "Menon P, Geevasinga N, van den Bos M et al. Cortical hyperexcitability and disease spread in amyotrophic lateral sclerosis. European journal of neurology. 2017.", "doi": "10.1111/ene.13295", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/28436181/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28436181/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID28436181", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human longitudinal physiological", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Fifty sporadic-ALS patients show cortical hyperexcitability patterns aligned with subsequently mapped contiguous spread.", "what_it_does_not_show": "Longitudinal association does not selectively manipulate glutamatergic transmission or exclude shared pathology.", "confounders_present": [ "Longitudinal association does not selectively manipulate glutamatergic transmission or exclude shared pathology." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 37, "pmid": "32203578", "title": "Cortical interneuron-mediated inhibition delays the onset of amyotrophic lateral sclerosis.", "citation": "Khademullah CS, Aqrabawi AJ, Place KM et al. Cortical interneuron-mediated inhibition delays the onset of amyotrophic lateral sclerosis. Brain : a journal of neurology. 2020.", "doi": "10.1093/brain/awaa034", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/32203578/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32203578/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID32203578", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal engineered", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Chemogenetic cortical parvalbumin-interneuron activation reduces pyramidal hyperexcitability and improves onset, neuronal and survival outcomes in SOD1 mice.", "what_it_does_not_show": "Cortical circuit modulation differs from spinal motor-neuron silencing; engineered disease and broad network effects limit human inference.", "confounders_present": [ "Cortical circuit modulation differs from spinal motor-neuron silencing; engineered disease and broad network effects limit human inference." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 38, "pmid": "27383069", "title": "Axonal Dysfunction Precedes Motor Neuronal Death in Amyotrophic Lateral Sclerosis.", "citation": "Iwai Y, Shibuya K, Misawa S et al. Axonal Dysfunction Precedes Motor Neuronal Death in Amyotrophic Lateral Sclerosis. PloS one. 2016.", "doi": "10.1371/journal.pone.0158596", "pmcid": "PMC4934877", "url": "https://pubmed.ncbi.nlm.nih.gov/27383069/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27383069/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID27383069", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "human physiological", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Nerve-excitability measures are abnormal in 140 ALS patients, including subgroups with normal CMAP.", "what_it_does_not_show": "CMAP is an indirect and insensitive loss measure; sodium/potassium conductances are not uniquely glutamate-driven.", "confounders_present": [ "CMAP is an indirect and insensitive loss measure; sodium/potassium conductances are not uniquely glutamate-driven." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 39, "pmid": "8302340", "title": "A controlled trial of riluzole in amyotrophic lateral sclerosis. ALS/Riluzole Study Group.", "citation": "Bensimon G, Lacomblez L, Meininger V et al. A controlled trial of riluzole in amyotrophic lateral sclerosis. ALS/Riluzole Study Group. The New England journal of medicine. 1994.", "doi": "10.1056/NEJM199403033300901", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/8302340/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/8302340/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID8302340", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4", "SC5" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "A 155-patient placebo-controlled riluzole trial found a survival advantage and slower strength deterioration.", "what_it_does_not_show": "Riluzole has multiple receptor/channel actions; benefit does not identify EAAT2 or AMPA as the necessary causal mediator.", "confounders_present": [ "Riluzole has multiple receptor/channel actions; benefit does not identify EAAT2 or AMPA as the necessary causal mediator." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 40, "pmid": "9851653", "title": "Riluzole has no acute effect on motor unit parameters in ALS.", "citation": "Desai J, Sharief M, Swash M et al. Riluzole has no acute effect on motor unit parameters in ALS. Journal of the neurological sciences. 1998.", "doi": "10.1016/s0022-510x(98)00201-9", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/9851653/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/9851653/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID9851653", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "null", "what_it_shows": "Acute randomized crossover testing did not show a riluzole effect on assessed motor-unit parameters.", "what_it_does_not_show": "Acute physiological null does not negate long-term survival benefit; abstract reports limited outcome detail.", "confounders_present": [ "Acute physiological null does not negate long-term survival benefit; abstract reports limited outcome detail." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 41, "pmid": "21983205", "title": "CSF from amyotrophic lateral sclerosis patients produces glutamate independent death of rat motor brain cortical neurons: protection by resveratrol but not riluzole.", "citation": "Yáñez M, Galán L, Matías-Guiu J et al. CSF from amyotrophic lateral sclerosis patients produces glutamate independent death of rat motor brain cortical neurons: protection by resveratrol but not riluzole. Brain research. 2011.", "doi": "10.1016/j.brainres.2011.09.025", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/21983205/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/21983205/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID21983205", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4", "SC5" ], "favors_models": [], "evidence_class": "Weak", "system": "human CSF in culture", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "ALS CSF damages cultured rat cortical neurons through an apparently glutamate-independent route; riluzole does not protect.", "what_it_does_not_show": "Cross-species cultured bioassay and pleiotropic resveratrol rescue do not establish the alternative mechanism in patients.", "confounders_present": [ "Cross-species cultured bioassay and pleiotropic resveratrol rescue do not establish the alternative mechanism in patients." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 42, "pmid": "19961264", "title": "A phase II trial of talampanel in subjects with amyotrophic lateral sclerosis.", "citation": "Pascuzzi RM, Shefner J, Chappell AS et al. A phase II trial of talampanel in subjects with amyotrophic lateral sclerosis. Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases. 2010.", "doi": "10.3109/17482960903307805", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/19961264/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/19961264/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID19961264", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "null", "what_it_shows": "Talampanel phase II randomized 59 ALS participants; favorable numerical strength/ALSFRS trends did not reach statistical significance.", "what_it_does_not_show": "Small trial and sedation/dizziness constrain inference; numerical trends are not demonstrated disease modification.", "confounders_present": [ "Small trial and sedation/dizziness constrain inference; numerical trends are not demonstrated disease modification." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 43, "pmid": "40132594", "title": "Single-cell transcriptomic and functional studies identify glial state changes and a role for inflammatory RIPK1 signaling in ALS pathogenesis.", "citation": "Zelic M, Blazier A, Pontarelli F et al. Single-cell transcriptomic and functional studies identify glial state changes and a role for inflammatory RIPK1 signaling in ALS pathogenesis. Immunity. 2025.", "doi": "10.1016/j.immuni.2025.02.024", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/40132594/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40132594/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID40132594", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "human tissue and animal", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Single-nucleus spinal profiles identify inflammatory glial states; RIPK1 blockade delays SOD1-mouse symptoms and modulates responses.", "what_it_does_not_show": "Independent inflammatory pathway is a rival/convergent contributor; human secreted-marker modulation is not patient survival causation.", "confounders_present": [ "Independent inflammatory pathway is a rival/convergent contributor; human secreted-marker modulation is not patient survival causation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 44, "pmid": "29606582", "title": "Kir4.1-Dependent Astrocyte-Fast Motor Neuron Interactions Are Required for Peak Strength.", "citation": "Kelley KW, Ben Haim L, Schirmer L et al. Kir4.1-Dependent Astrocyte-Fast Motor Neuron Interactions Are Required for Peak Strength. Neuron. 2018.", "doi": "10.1016/j.neuron.2018.03.010", "pmcid": "PMC5919779", "url": "https://pubmed.ncbi.nlm.nih.gov/29606582/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29606582/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID29606582", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC5" ], "favors_models": [], "evidence_class": "Strong", "system": "animal endogenous lesion", "decisive_perturbation": true, "endogenous": true, "direction": "contradicts", "what_it_shows": "Astrocytic Kir4.1 loss reduces peak strength and changes fast-motor-neuron size but is dispensable for survival even in SOD1 background.", "what_it_does_not_show": "Distinct potassium-support pathway; illustrates strength/death decoupling rather than refuting astrocytic glutamate clearance.", "confounders_present": [ "Distinct potassium-support pathway; illustrates strength/death decoupling rather than refuting astrocytic glutamate clearance." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 45, "pmid": "34140581", "title": "GLT1 gene delivery based on bone marrow-derived cells ameliorates motor function and survival in a mouse model of ALS.", "citation": "Ohashi N, Terashima T, Katagi M et al. GLT1 gene delivery based on bone marrow-derived cells ameliorates motor function and survival in a mouse model of ALS. Scientific reports. 2021.", "doi": "10.1038/s41598-021-92285-x", "pmcid": "PMC8211665", "url": "https://pubmed.ncbi.nlm.nih.gov/34140581/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34140581/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID34140581", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal engineered", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "GLT1-expressing transplanted marrow-derived cells improve mouse motor behavior and survival and shift inflammatory markers.", "what_it_does_not_show": "Transplantation and immune-state changes prevent clean attribution to astrocytic transporter correction alone.", "confounders_present": [ "Transplantation and immune-state changes prevent clean attribution to astrocytic transporter correction alone." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 46, "pmid": "26621731", "title": "Translational profiling identifies a cascade of damage initiated in motor neurons and spreading to glia in mutant SOD1-mediated ALS.", "citation": "Sun S, Sun Y, Ling SC et al. Translational profiling identifies a cascade of damage initiated in motor neurons and spreading to glia in mutant SOD1-mediated ALS. Proceedings of the National Academy of Sciences of the United States of America. 2015.", "doi": "10.1073/pnas.1520639112", "pmcid": "PMC4687558", "url": "https://pubmed.ncbi.nlm.nih.gov/26621731/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26621731/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID26621731", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal engineered", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Cell-type translational profiles place early SOD1-linked synaptic/metabolic/ER changes in motor neurons before later glial changes.", "what_it_does_not_show": "SOD1 ordering is not common sporadic ordering; profiles do not directly block glutamate as a downstream contributor.", "confounders_present": [ "SOD1 ordering is not common sporadic ordering; profiles do not directly block glutamate as a downstream contributor." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 47, "pmid": "35197626", "title": "TDP-43 represses cryptic exon inclusion in the FTD-ALS gene UNC13A.", "citation": "Ma XR, Prudencio M, Koike Y et al. TDP-43 represses cryptic exon inclusion in the FTD-ALS gene UNC13A. Nature. 2022.", "doi": "10.1038/s41586-022-04424-7", "pmcid": "PMC8891019", "url": "https://pubmed.ncbi.nlm.nih.gov/35197626/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35197626/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "TDP43-UNC13A-independent-report-A", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "human neuronal and tissue", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "TDP-43 loss activates a UNC13A cryptic exon; ALS-risk variants increase mis-splicing and reduce protein.", "what_it_does_not_show": "Supports a functional genetic/RNA rival, not proof that all neuronal death is independent of excitotoxicity.", "confounders_present": [ "Supports a functional genetic/RNA rival, not proof that all neuronal death is independent of excitotoxicity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 48, "pmid": "35197628", "title": "TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A.", "citation": "Brown AL, Wilkins OG, Keuss MJ et al. TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A. Nature. 2022.", "doi": "10.1038/s41586-022-04436-3", "pmcid": "PMC8891020", "url": "https://pubmed.ncbi.nlm.nih.gov/35197628/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35197628/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID38890465" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "TDP43-UNC13A-independent-report-B", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "human neuronal and tissue", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Independent experiments link UNC13A risk variants to TDP-43-dependent cryptic splicing and protein depletion.", "what_it_does_not_show": "Related human tissues and TDP-43 platforms may overlap; linked erratum PMID38890465 is recorded but details not examined.", "confounders_present": [ "Related human tissues and TDP-43 platforms may overlap; linked erratum PMID38890465 is recorded but details not examined." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 49, "pmid": "36927019", "title": "Mechanism of STMN2 cryptic splice-polyadenylation and its correction for TDP-43 proteinopathies.", "citation": "Baughn MW, Melamed Z, López-Erauskin J et al. Mechanism of STMN2 cryptic splice-polyadenylation and its correction for TDP-43 proteinopathies. Science (New York, N.Y.). 2023.", "doi": "10.1126/science.abq5622", "pmcid": "PMC10148063", "url": "https://pubmed.ncbi.nlm.nih.gov/36927019/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36927019/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "TDP43-STMN2-research-line", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "human neuronal and animal", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "STMN2 cryptic processing is corrected by targeted reagents; axonal regeneration/lysosome trafficking recover in deficient human motor neurons.", "what_it_does_not_show": "Functional axon repair and engineered humanized mice are not broad clinical survival proof.", "confounders_present": [ "Functional axon repair and engineered humanized mice are not broad clinical survival proof." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 50, "pmid": "30643298", "title": "Premature polyadenylation-mediated loss of stathmin-2 is a hallmark of TDP-43-dependent neurodegeneration.", "citation": "Melamed Z, López-Erauskin J, Baughn MW et al. Premature polyadenylation-mediated loss of stathmin-2 is a hallmark of TDP-43-dependent neurodegeneration. Nature neuroscience. 2019.", "doi": "10.1038/s41593-018-0293-z", "pmcid": "PMC6348009", "url": "https://pubmed.ncbi.nlm.nih.gov/30643298/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30643298/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "TDP43-STMN2-research-line", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "human neuronal and tissue", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Loss of TDP-43 reduces STMN2 through premature polyadenylation; STMN2 restoration rescues axonal regenerative capacity.", "what_it_does_not_show": "Axonal regeneration is a bounded functional endpoint, not death prevention in all ALS.", "confounders_present": [ "Axonal regeneration is a bounded functional endpoint, not death prevention in all ALS." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 51, "pmid": "30643292", "title": "ALS-implicated protein TDP-43 sustains levels of STMN2, a mediator of motor neuron growth and repair.", "citation": "Klim JR, Williams LA, Limone F et al. ALS-implicated protein TDP-43 sustains levels of STMN2, a mediator of motor neuron growth and repair. Nature neuroscience. 2019.", "doi": "10.1038/s41593-018-0300-4", "pmcid": "PMC7153761", "url": "https://pubmed.ncbi.nlm.nih.gov/30643292/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30643292/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "TDP43-STMN2-research-line", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "human neuronal and tissue", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "TDP-43/STMN2 perturbation and stabilization connect transcript loss to neurite and regeneration deficits.", "what_it_does_not_show": "Shares disease pathway with other STMN2 reports; restoration is not independent clinical causality.", "confounders_present": [ "Shares disease pathway with other STMN2 reports; restoration is not independent clinical causality." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 52, "pmid": "35294901", "title": "Loss of mouse Stmn2 function causes motor neuropathy.", "citation": "Guerra San Juan I, Nash LA, Smith KS et al. Loss of mouse Stmn2 function causes motor neuropathy. Neuron. 2022.", "doi": "10.1016/j.neuron.2022.02.011", "pmcid": "PMC9119928", "url": "https://pubmed.ncbi.nlm.nih.gov/35294901/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35294901/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID36480942" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID35294901", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4", "SC5" ], "favors_models": [], "evidence_class": "Strong", "system": "animal endogenous lesion", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Endogenous Stmn2 loss causes denervation and motor dysfunction; human STMN2 BAC rescues motor phenotypes.", "what_it_does_not_show": "Different axonal-support lesion, not selective neuron death caused by glutamate. Linked erratum PMID36480942 remains an unexamined detail.", "confounders_present": [ "Different axonal-support lesion, not selective neuron death caused by glutamate. Linked erratum PMID36480942 remains an unexamined detail." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 53, "pmid": "31661035", "title": "Sarm1 deletion suppresses TDP-43-linked motor neuron degeneration and cortical spine loss.", "citation": "White MA, Lin Z, Kim E et al. Sarm1 deletion suppresses TDP-43-linked motor neuron degeneration and cortical spine loss. Acta neuropathologica communications. 2019.", "doi": "10.1186/s40478-019-0800-9", "pmcid": "PMC6819591", "url": "https://pubmed.ncbi.nlm.nih.gov/31661035/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31661035/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID31661035", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal engineered", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Sarm1 deletion attenuates TDP-43-model axon/neuromuscular-junction and neuron loss, but not behavioral deficits.", "what_it_does_not_show": "Mixed FTD-like model and sex-related viability affect scope; phenotype classes must not be collapsed.", "confounders_present": [ "Mixed FTD-like model and sex-related viability affect scope; phenotype classes must not be collapsed." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 54, "pmid": "25944722", "title": "AMPA receptor activation causes preferential mitochondrial Ca²⁺ load and oxidative stress in motor neurons.", "citation": "Joshi DC, Tewari BP, Singh M et al. AMPA receptor activation causes preferential mitochondrial Ca²⁺ load and oxidative stress in motor neurons. Brain research. 2015.", "doi": "10.1016/j.brainres.2015.04.042", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/25944722/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25944722/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID25944722", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Weak", "system": "in vitro", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "AMPA stimulation preferentially loads motor-neuron mitochondria and produces sustained oxidative stress.", "what_it_does_not_show": "Forced cultured challenge supports calcium/mitochondrial plausibility without endogenous disease necessity.", "confounders_present": [ "Forced cultured challenge supports calcium/mitochondrial plausibility without endogenous disease necessity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 55, "pmid": "34322897", "title": "An open label pilot study of the safety and tolerability of perampanel in amyotrophic lateral sclerosis.", "citation": "Hotait M, Ismail HH, Saab GE et al. An open label pilot study of the safety and tolerability of perampanel in amyotrophic lateral sclerosis. Muscle & nerve. 2021.", "doi": "10.1002/mus.27385", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/34322897/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34322897/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID34322897", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "human open label", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "All six ALS participants had adverse events on perampanel; four withdrew and the pilot stopped.", "what_it_does_not_show": "Tiny uncontrolled tolerability study cannot estimate efficacy but challenges unqualified translational optimism.", "confounders_present": [ "Tiny uncontrolled tolerability study cannot estimate efficacy but challenges unqualified translational optimism." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 56, "pmid": "34107252", "title": "Human amyotrophic lateral sclerosis excitability phenotype screen: Target discovery and validation.", "citation": "Huang X, Roet KCD, Zhang L et al. Human amyotrophic lateral sclerosis excitability phenotype screen: Target discovery and validation. Cell reports. 2021.", "doi": "10.1016/j.celrep.2021.109224", "pmcid": "PMC8209673", "url": "https://pubmed.ncbi.nlm.nih.gov/34107252/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34107252/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID34107252", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC5" ], "favors_models": [], "evidence_class": "Weak", "system": "in vitro", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "A target-annotated compound screen identifies AMPA, Kv7 and D2 modulation of patient-derived motor-neuron excitability.", "what_it_does_not_show": "Cell excitability screens are target-discovery evidence, not organismal neuronal rescue.", "confounders_present": [ "Cell excitability screens are target-discovery evidence, not organismal neuronal rescue." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 57, "pmid": "29380416", "title": "Astrocytes expressing ALS-linked mutant FUS induce motor neuron death through release of tumor necrosis factor-alpha.", "citation": "Kia A, McAvoy K, Krishnamurthy K et al. Astrocytes expressing ALS-linked mutant FUS induce motor neuron death through release of tumor necrosis factor-alpha. Glia. 2018.", "doi": "10.1002/glia.23298", "pmcid": "PMC5873384", "url": "https://pubmed.ncbi.nlm.nih.gov/29380416/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29380416/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID29380416", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC5" ], "favors_models": [], "evidence_class": "Weak", "system": "in vitro", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Mutant-FUS astrocyte conditioned medium kills neurons; TNF neutralization blocks toxicity and receptor composition changes accompany it.", "what_it_does_not_show": "Tagged forced FUS and culture constrain inference; inflammatory and AMPA routes can be coupled rather than exclusive.", "confounders_present": [ "Tagged forced FUS and culture constrain inference; inflammatory and AMPA routes can be coupled rather than exclusive." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 58, "pmid": "30007309", "title": "Motor neuron-derived microRNAs cause astrocyte dysfunction in amyotrophic lateral sclerosis.", "citation": "Hoye ML, Regan MR, Jensen LA et al. Motor neuron-derived microRNAs cause astrocyte dysfunction in amyotrophic lateral sclerosis. Brain : a journal of neurology. 2018.", "doi": "10.1093/brain/awy182", "pmcid": "PMC6113638", "url": "https://pubmed.ncbi.nlm.nih.gov/30007309/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30007309/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID30007309", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal and culture", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Motor-neuron-derived extracellular miR-218 lowers astrocytic EAAT2; antisense inhibition mitigates changes in ALS mice.", "what_it_does_not_show": "Shows an upstream neuron-to-astrocyte feedback alternative; transporter-marker rescue is not demonstrated survival benefit in the examined abstract.", "confounders_present": [ "Shows an upstream neuron-to-astrocyte feedback alternative; transporter-marker rescue is not demonstrated survival benefit in the examined abstract." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 59, "pmid": "22801498", "title": "Oligodendroglia metabolically support axons and contribute to neurodegeneration.", "citation": "Lee Y, Morrison BM, Li Y et al. Oligodendroglia metabolically support axons and contribute to neurodegeneration. Nature. 2012.", "doi": "10.1038/nature11314", "pmcid": "PMC3408792", "url": "https://pubmed.ncbi.nlm.nih.gov/22801498/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/22801498/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID22801498", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4", "SC5" ], "favors_models": [], "evidence_class": "Strong", "system": "animal endogenous lesion and human tissue", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Disrupting oligodendroglial MCT1 injures axons/neurons, and MCT1 is reduced in ALS materials.", "what_it_does_not_show": "Independent metabolic-support route; its presence does not exclude interacting glutamate stress or establish universal primacy.", "confounders_present": [ "Independent metabolic-support route; its presence does not exclude interacting glutamate stress or establish universal primacy." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 60, "pmid": "28342750", "title": "Mutation of the caspase-3 cleavage site in the astroglial glutamate transporter EAAT2 delays disease progression and extends lifespan in the SOD1-G93A mouse model of ALS.", "citation": "Rosenblum LT, Shamamandri-Markandaiah S, Ghosh B et al. Mutation of the caspase-3 cleavage site in the astroglial glutamate transporter EAAT2 delays disease progression and extends lifespan in the SOD1-G93A mouse model of ALS. Experimental neurology. 2017.", "doi": "10.1016/j.expneurol.2017.03.014", "pmcid": "PMC5433801", "url": "https://pubmed.ncbi.nlm.nih.gov/28342750/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28342750/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID28342750", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 2:RESULTS:paragraph1, 2:RESULTS:paragraph2, 2:RESULTS:paragraph6, 2:RESULTS:paragraph8, 2:RESULTS:paragraph9, 2:RESULTS:paragraph10, 2:RESULTS:paragraph13, 2:RESULTS:paragraph14. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC5" ], "favors_models": [], "evidence_class": "Strong", "system": "animal endogenous mediator", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Mouse endogenous EAAT2-D504N blocks cleavage; progression and lifespan improve modestly in SOD1-G93A mice with matched transgene-copy checks.", "what_it_does_not_show": "Human plasmid D505N and mouse D504N name homologous sites. Onset and measured P150 motor-neuron counts did not change; reducing toxic CTE-SUMO1 is not uniquely restoring glutamate clearance.", "confounders_present": [ "Human plasmid D505N and mouse D504N name homologous sites. Onset and measured P150 motor-neuron counts did not change; reducing toxic CTE-SUMO1 is not uniquely restoring glutamate clearance." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 61, "pmid": "29458024", "title": "Spinal cord-specific deletion of the glutamate transporter GLT1 causes motor neuron death in mice.", "citation": "Sugiyama K, Tanaka K et al. Spinal cord-specific deletion of the glutamate transporter GLT1 causes motor neuron death in mice. Biochemical and biophysical research communications. 2018.", "doi": "10.1016/j.bbrc.2018.02.132", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/29458024/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29458024/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID29458024", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "animal endogenous lesion", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Hoxb8-Cre spinal GLT1 deletion produces motor deficits and motor-neuron loss.", "what_it_does_not_show": "Original abstract supports sufficiency within forced spinal deletion; Methods/Results not retrieved by Consensus or local PMC. Developmental timing and matched rescue details remain unverified.", "confounders_present": [ "Original abstract supports sufficiency within forced spinal deletion; Methods/Results not retrieved by Consensus or local PMC. Developmental timing and matched rescue details remain unverified." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 62, "pmid": "20372915", "title": "TDP-43 pathology in sporadic ALS occurs in motor neurons lacking the RNA editing enzyme ADAR2.", "citation": "Aizawa H, Sawada J, Hideyama T et al. TDP-43 pathology in sporadic ALS occurs in motor neurons lacking the RNA editing enzyme ADAR2. Acta neuropathologica. 2010.", "doi": "10.1007/s00401-010-0678-x", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/20372915/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/20372915/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID20372915", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4" ], "favors_models": [], "evidence_class": "Weak", "system": "human postmortem", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "ADAR2-negative ALS motor neurons contain phosphorylated cytoplasmic TDP-43 and lack normal nuclear TDP-43.", "what_it_does_not_show": "Colocalization does not order the lesions; surviving postmortem cells are selected.", "confounders_present": [ "Colocalization does not order the lesions; surviving postmortem cells are selected." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 63, "pmid": "7611729", "title": "Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis.", "citation": "Rothstein JD, Van Kammen M, Levey AI et al. Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis. Annals of neurology. 1995.", "doi": "10.1002/ana.410380114", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/7611729/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/7611729/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID7611729", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human postmortem", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Matched-age/postmortem-delay specimens show selective GLT1 protein loss compared with other transporters and stable GFAP.", "what_it_does_not_show": "Authors explicitly permit primary defect, downregulation or other toxicity; stable GFAP is not proof of intact astrocytic function.", "confounders_present": [ "Authors explicitly permit primary defect, downregulation or other toxicity; stable GFAP is not proof of intact astrocytic function." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 64, "pmid": "33226425", "title": "Effect of Ezogabine on Cortical and Spinal Motor Neuron Excitability in Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial.", "citation": "Wainger BJ, Macklin EA, Vucic S et al. Effect of Ezogabine on Cortical and Spinal Motor Neuron Excitability in Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial. JAMA neurology. 2021.", "doi": "10.1001/jamaneurol.2020.4300", "pmcid": "PMC7684515", "url": "https://pubmed.ncbi.nlm.nih.gov/33226425/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33226425/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID33226425", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Publisher HTML paragraphs:paragraph45, 0:Publisher HTML paragraphs:paragraph47, 0:Publisher HTML paragraphs:paragraph49, 0:Publisher HTML paragraphs:paragraph52, 0:Publisher HTML paragraphs:paragraph55, 0:Publisher HTML paragraphs:paragraph60, 0:Publisher HTML paragraphs:paragraph69, 0:Publisher HTML paragraphs:paragraph70, 0:Publisher HTML paragraphs:paragraph77, 0:Publisher HTML paragraphs:paragraph79. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC5" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Ezogabine randomized 65 ALS participants, changes cortical/axonal excitability, and showed no significant ALSFRS-R, vital-capacity or strength effect over the short trial.", "what_it_does_not_show": "Only four weeks at full dose; this cannot establish durable efficacy or refute a long-term effect. Active-arm discontinuation and biomarker selection constrain generalization.", "confounders_present": [ "Only four weeks at full dose; this cannot establish durable efficacy or refute a long-term effect. Active-arm discontinuation and biomarker selection constrain generalization." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 65, "pmid": "29672831", "title": "Acute Effects of Riluzole and Retigabine on Axonal Excitability in Patients With Amyotrophic Lateral Sclerosis: A Randomized, Double-Blind, Placebo-Controlled, Crossover Trial.", "citation": "Kovalchuk MO, Heuberger JAAC, Sleutjes BTHM et al. Acute Effects of Riluzole and Retigabine on Axonal Excitability in Patients With Amyotrophic Lateral Sclerosis: A Randomized, Double-Blind, Placebo-Controlled, Crossover Trial. Clinical pharmacology and therapeutics. 2018.", "doi": "10.1002/cpt.1096", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/29672831/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29672831/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID29672831", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "An 18-person acute crossover shows retigabine axonal-excitability effects but no riluzole effect on those metrics.", "what_it_does_not_show": "Single-dose physiology cannot identify the mediator of long-term survival benefit.", "confounders_present": [ "Single-dose physiology cannot identify the mediator of long-term survival benefit." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 66, "pmid": "24703839", "title": "Intrinsic membrane hyperexcitability of amyotrophic lateral sclerosis patient-derived motor neurons.", "citation": "Wainger BJ, Kiskinis E, Mellin C et al. Intrinsic membrane hyperexcitability of amyotrophic lateral sclerosis patient-derived motor neurons. Cell reports. 2014.", "doi": "10.1016/j.celrep.2014.03.019", "pmcid": "PMC4023477", "url": "https://pubmed.ncbi.nlm.nih.gov/24703839/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24703839/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID24703839", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "human cultured isogenic", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "SOD1, C9orf72 and FUS iPSC neurons show hyperexcitability; isogenic SOD1 correction removes it and retigabine improves mutant-cell survival.", "what_it_does_not_show": "Genetic correction validates genotype dependence, while immature cultures and Kv7 effects do not prove common adult glutamatergic primacy.", "confounders_present": [ "Genetic correction validates genotype dependence, while immature cultures and Kv7 effects do not prove common adult glutamatergic primacy." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 67, "pmid": "24094105", "title": "Neuroprotection through excitability and mTOR required in ALS motoneurons to delay disease and extend survival.", "citation": "Saxena S, Roselli F, Singh K et al. Neuroprotection through excitability and mTOR required in ALS motoneurons to delay disease and extend survival. Neuron. 2013.", "doi": "10.1016/j.neuron.2013.07.027", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/24094105/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24094105/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID24094105", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal engineered", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Enhancing susceptible motor-neuron excitability/mTOR protects in SOD1 models; reducing it worsens pathology and disease.", "what_it_does_not_show": "Stage and motor-pool dependence challenge uniform hyperexcitability toxicity, without excluding excessive calcium flux in other contexts.", "confounders_present": [ "Stage and motor-pool dependence challenge uniform hyperexcitability toxicity, without excluding excessive calcium flux in other contexts." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 68, "pmid": "14736504", "title": "Amyotrophic lateral sclerosis is a distal axonopathy: evidence in mice and man.", "citation": "Fischer LR, Culver DG, Tennant P et al. Amyotrophic lateral sclerosis is a distal axonopathy: evidence in mice and man. Experimental neurology. 2004.", "doi": "10.1016/j.expneurol.2003.10.004", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/14736504/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/14736504/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID14736504", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal and one human autopsy", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "SOD1 mice show distal denervation before axon and cell-body loss; one human autopsy has denervation with preserved-appearing neurons.", "what_it_does_not_show": "Temporal compartment ordering is limited by one human case and does not test glutamate directly; distal injury is not necessarily glutamate independent.", "confounders_present": [ "Temporal compartment ordering is limited by one human case and does not test glutamate directly; distal injury is not necessarily glutamate independent." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 69, "pmid": "8676624", "title": "Dose-ranging study of riluzole in amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis/Riluzole Study Group II.", "citation": "Lacomblez L, Bensimon G, Leigh PN et al. Dose-ranging study of riluzole in amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis/Riluzole Study Group II. Lancet (London, England). 1996.", "doi": "10.1016/s0140-6736(96)91680-3", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/8676624/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/8676624/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID8676624", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4", "SC5" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "The 959-person riluzole dose-ranging trial supports survival benefit; the prespecified 100-mg comparison differs before versus after prognostic adjustment.", "what_it_does_not_show": "Unadjusted p=.076 versus adjusted p=.002 and no separating functional scale deserve context; a multi-action drug is not selective mechanism proof.", "confounders_present": [ "Unadjusted p=.076 versus adjusted p=.002 and no separating functional scale deserve context; a multi-action drug is not selective mechanism proof." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] } ], "verification_summary": { "load_bearing_claims_checked": 75, "verified": 75, "unverified": 0, "contradicted": 0, "note": "Verified attribution is distinct from mechanism truth or complete body access." }, "factual_issues_found": [], "cap_rules_applied": [ { "subclaim_id": "SC1", "cap": "Β", "cap_source": "rubric", "triggered": true, "trigger_text_quoted": "Operational rule: association without temporal or perturbational proof caps at Β.", "specific_trigger": "Β: selective transporter loss, editing defects and excitability patterns are reproducible but spatial/postmortem associations cannot determine disease dependency.", "resulting_ceiling": "Β" }, { "subclaim_id": "SC4", "cap": "Γ", "cap_source": "rubric", "triggered": true, "trigger_text_quoted": "Maximum if mechanism is biologically plausible, supported by in vitro or simplified animal paradigms, but no disease-relevant necessity is shown in vivo.", "specific_trigger": "Γ: human tissue and physiology plus model causality make the proposed obligate driver plausible, but no selective correction demonstrates sporadic-human disease dependency; clinical null/harm and stage-dependent protective excitation remain material separators.", "resulting_ceiling": "Γ" }, { "subclaim_id": "SC5", "cap": "Γ", "cap_source": "rubric", "triggered": true, "trigger_text_quoted": "Maximum if mechanism is biologically plausible, supported by in vitro or simplified animal paradigms, but no disease-relevant necessity is shown in vivo.", "specific_trigger": "Γ: familial/cell-specific models and human-associated signatures do not converge on universal progression dependence. Riluzole benefit is real but multi-action; perampanel and ceftriaxone do not supply the missing selective clinical test.", "resulting_ceiling": "Γ" } ], "cap_precedence_resolutions": [ { "collision": "Perturbation in a defined setting versus broader inference", "subclaim_scope_cap_binds_on": "Excitotoxicity—excess glutamatergic signaling from impaired astrocytic EAAT2/GLT-1 clearance and calcium-permeable AMPA receptors—is the causal driver of motor-neuron death in ALS.", "subclaim_scope_threshold_binds_on": "The precise experimentally tested subclaim scope", "resolution": "01-neurodegeneration thresholds bind the forced endogenous-lesion SC2 and precise SOD1 progression SC3. Γ constrains the inference to SC4/SC5 human disease dependency; it does not erase narrow genetic rescue. Conversely, improvement in engineered disease cannot transfer a higher score to sporadic primacy.", "note": "Convergent lines are assessed as a set; one weak leg is not re-capped over the assembled case." } ], "boundary_check_BGD": [ { "subclaim_id": "SC1", "field_valid_perturbation_quote": "\n- Endogenous genetic deletion, suppression, or degron depletion of the proposed mediator in vivo\n- Selective pathway inhibition that changes onset/progression while preserving broader viability\n- Vagotomy-type natural experiment, only if confounding is rigorously controlled AND effect is disease-initiation relevant rather than merely associated", "qualifying_evidence_present": "no", "qualifying_evidence_citation": "PMID33226425", "gamma_hard_rules_triggered": [ "Cultured agonist toxicity and engineered receptor/transporter systems alone cannot carry sporadic-human primacy.", "Endogenous mediator perturbations retain real within-model value; forced disease background, developmental timing, cell role and drug target engagement limit broader inference." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "Β: selective transporter loss, editing defects and excitability patterns are reproducible but spatial/postmortem associations cannot determine disease dependency.", "ceiling_from_boundary_check": "Γ" }, { "subclaim_id": "SC2", "field_valid_perturbation_quote": "\n- Endogenous genetic deletion, suppression, or degron depletion of the proposed mediator in vivo\n- Selective pathway inhibition that changes onset/progression while preserving broader viability\n- Vagotomy-type natural experiment, only if confounding is rigorously controlled AND effect is disease-initiation relevant rather than merely associated", "qualifying_evidence_present": "yes", "qualifying_evidence_citation": "PMID31112137, PMID40860154, PMID24115583, PMID27350567, PMID35022247, PMID17804792, PMID20826656, PMID19185395, PMID18617894, PMID32203578, PMID29606582, PMID29380416, PMID29458024, PMID24703839", "gamma_hard_rules_triggered": [ "Cultured agonist toxicity and engineered receptor/transporter systems alone cannot carry sporadic-human primacy.", "Endogenous mediator perturbations retain real within-model value; forced disease background, developmental timing, cell role and drug target engagement limit broader inference." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "yes", "perturbation_result_note": "Ζ: distinct endogenous ADAR2 and spinal GLT1 lesions produce motor phenotypes; endogenous edited-GluR2 rescue in AR2 narrows the major ADAR2 off-target alternative. Membralin/EAAT2 rescue adds a different glial pathway. This scope is forced-lesion sufficiency, not spontaneous disease primacy.", "ceiling_from_boundary_check": "Δ or higher" }, { "subclaim_id": "SC3", "field_valid_perturbation_quote": "\n- Endogenous genetic deletion, suppression, or degron depletion of the proposed mediator in vivo\n- Selective pathway inhibition that changes onset/progression while preserving broader viability\n- Vagotomy-type natural experiment, only if confounding is rigorously controlled AND effect is disease-initiation relevant rather than merely associated", "qualifying_evidence_present": "yes", "qualifying_evidence_citation": "PMID24569372, PMID34140581, PMID28342750", "gamma_hard_rules_triggered": [ "Cultured agonist toxicity and engineered receptor/transporter systems alone cannot carry sporadic-human primacy.", "Endogenous mediator perturbations retain real within-model value; forced disease background, developmental timing, cell role and drug target engagement limit broader inference." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "yes", "perturbation_result_note": "Ε: endogenous caspase-resistant EAAT2 knock-in changes functional progression and survival in the defined SOD1-G93A context. Transport kinetics and transgene-copy controls strengthen attribution, while absent onset/neuron-count effects and toxic-fragment mechanisms restrict the causal claim.", "ceiling_from_boundary_check": "Δ or higher" }, { "subclaim_id": "SC4", "field_valid_perturbation_quote": "\n- Endogenous genetic deletion, suppression, or degron depletion of the proposed mediator in vivo\n- Selective pathway inhibition that changes onset/progression while preserving broader viability\n- Vagotomy-type natural experiment, only if confounding is rigorously controlled AND effect is disease-initiation relevant rather than merely associated", "qualifying_evidence_present": "no", "qualifying_evidence_citation": "PMID25297012, PMID34191081, PMID32484501, PMID8302340, PMID19961264, PMID40132594, PMID35197626, PMID35197628, PMID36927019, PMID30643298, PMID30643292, PMID35294901, PMID31661035, PMID30007309, PMID22801498, PMID24094105, PMID8676624", "gamma_hard_rules_triggered": [ "Cultured agonist toxicity and engineered receptor/transporter systems alone cannot carry sporadic-human primacy.", "Endogenous mediator perturbations retain real within-model value; forced disease background, developmental timing, cell role and drug target engagement limit broader inference." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "Γ: human tissue and physiology plus model causality make the proposed obligate driver plausible, but no selective correction demonstrates sporadic-human disease dependency; clinical null/harm and stage-dependent protective excitation remain material separators.", "ceiling_from_boundary_check": "Γ" }, { "subclaim_id": "SC5", "field_valid_perturbation_quote": "\n- Endogenous genetic deletion, suppression, or degron depletion of the proposed mediator in vivo\n- Selective pathway inhibition that changes onset/progression while preserving broader viability\n- Vagotomy-type natural experiment, only if confounding is rigorously controlled AND effect is disease-initiation relevant rather than merely associated", "qualifying_evidence_present": "no", "qualifying_evidence_citation": "PMID31112137, PMID24569372, PMID40860154, PMID25297012, PMID34191081, PMID20826656, PMID18617894, PMID32484501, PMID32203578, PMID8302340, PMID19961264, PMID40132594, PMID29606582, PMID34140581, PMID35197626, PMID35197628, PMID36927019, PMID30643298, PMID30643292, PMID35294901, PMID31661035, PMID29380416, PMID30007309, PMID22801498, PMID28342750, PMID33226425, PMID24703839, PMID24094105, PMID8676624", "gamma_hard_rules_triggered": [ "Cultured agonist toxicity and engineered receptor/transporter systems alone cannot carry sporadic-human primacy.", "Endogenous mediator perturbations retain real within-model value; forced disease background, developmental timing, cell role and drug target engagement limit broader inference." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "Γ: familial/cell-specific models and human-associated signatures do not converge on universal progression dependence. Riluzole benefit is real but multi-action; perampanel and ceftriaxone do not supply the missing selective clinical test.", "ceiling_from_boundary_check": "Γ" } ], "thresholds_tested": [ { "subclaim_id": "SC1", "threshold": "Δ", "requirement_quoted": "Requires at least one genuine causal perturbation in a disease-relevant in vivo system, or equivalent human natural experiment that materially supports the mechanism.", "satisfied": "no", "supporting_evidence": [ "[64] Ezogabine randomized 65 ALS participants, changes cortical/axonal excitability, and showed no significant ALSFRS-R, vital-capacity or strength effect over the short trial." ], "what_would_cross_it": "A selective, target-engaged perturbation matching SC1 with independently measured neuronal survival and functional trajectory, stage-matched controls and replication across prespecified contexts." }, { "subclaim_id": "SC2", "threshold": "Δ", "requirement_quoted": "Requires at least one genuine causal perturbation in a disease-relevant in vivo system, or equivalent human natural experiment that materially supports the mechanism.", "satisfied": "yes", "supporting_evidence": [ "[1] Astrocytic membralin loss lowers EAAT2 and causes motor phenotypes; restoring EAAT2 or membralin protects in engineered settings.", "[5] Astrocytic YAP loss exacerbates poly-GA-model phenotypes; LDN-212320 restores EAAT2 and partially rescues motor and neuronal readouts.", "[14] AAV9-ADAR2 delivery rescues motor-neuron loss, function and TDP-43 distribution in conditional ADAR2-deficient mice.", "[15] Perampanel protects motor and neuronal readouts in AR2 mice.", "[19] ICV AMPA aptamers improve motor and neuronal readouts in AR2 mice.", "[25] Ventral astrocytes regulate strain-dependent GluR2 and motor-neuron susceptibility; mutant SOD1 disrupts this capacity.", "[26] Conditional ADAR2 loss in a cholinergic motor-neuron subset causes slow neuronal loss; endogenous edited-GluR2 replacement preserves neurons and motor function despite ADAR2 absence.", "[30] VEGF induces GluR2 and lowers AMPA calcium permeability and vulnerability in cultured neurons; ICV treatment induces ventral-spinal expression.", "[31] Mutant-SOD1 astrocytes are mGluR5-vulnerable; in vivo mGluR5 blockade slows astrocyte damage and modestly delays disease.", "[37] Chemogenetic cortical parvalbumin-interneuron activation reduces pyramidal hyperexcitability and improves onset, neuronal and survival outcomes in SOD1 mice.", "[44] Astrocytic Kir4.1 loss reduces peak strength and changes fast-motor-neuron size but is dispensable for survival even in SOD1 background.", "[57] Mutant-FUS astrocyte conditioned medium kills neurons; TNF neutralization blocks toxicity and receptor composition changes accompany it.", "[61] Hoxb8-Cre spinal GLT1 deletion produces motor deficits and motor-neuron loss.", "[66] SOD1, C9orf72 and FUS iPSC neurons show hyperexcitability; isogenic SOD1 correction removes it and retigabine improves mutant-cell survival." ], "what_would_cross_it": "" }, { "subclaim_id": "SC2", "threshold": "Ε", "requirement_quoted": "Requires causal support in a defined context, but with clear restriction by subtype, disease stage, model, or tissue.\n\nUse Ε when there is a real causal contribution, but generalization to the entire disease class fails.", "satisfied": "yes", "supporting_evidence": [ "[1] Astrocytic membralin loss lowers EAAT2 and causes motor phenotypes; restoring EAAT2 or membralin protects in engineered settings.", "[5] Astrocytic YAP loss exacerbates poly-GA-model phenotypes; LDN-212320 restores EAAT2 and partially rescues motor and neuronal readouts.", "[14] AAV9-ADAR2 delivery rescues motor-neuron loss, function and TDP-43 distribution in conditional ADAR2-deficient mice.", "[15] Perampanel protects motor and neuronal readouts in AR2 mice.", "[19] ICV AMPA aptamers improve motor and neuronal readouts in AR2 mice.", "[25] Ventral astrocytes regulate strain-dependent GluR2 and motor-neuron susceptibility; mutant SOD1 disrupts this capacity.", "[26] Conditional ADAR2 loss in a cholinergic motor-neuron subset causes slow neuronal loss; endogenous edited-GluR2 replacement preserves neurons and motor function despite ADAR2 absence.", "[30] VEGF induces GluR2 and lowers AMPA calcium permeability and vulnerability in cultured neurons; ICV treatment induces ventral-spinal expression.", "[31] Mutant-SOD1 astrocytes are mGluR5-vulnerable; in vivo mGluR5 blockade slows astrocyte damage and modestly delays disease.", "[37] Chemogenetic cortical parvalbumin-interneuron activation reduces pyramidal hyperexcitability and improves onset, neuronal and survival outcomes in SOD1 mice.", "[44] Astrocytic Kir4.1 loss reduces peak strength and changes fast-motor-neuron size but is dispensable for survival even in SOD1 background.", "[57] Mutant-FUS astrocyte conditioned medium kills neurons; TNF neutralization blocks toxicity and receptor composition changes accompany it.", "[61] Hoxb8-Cre spinal GLT1 deletion produces motor deficits and motor-neuron loss.", "[66] SOD1, C9orf72 and FUS iPSC neurons show hyperexcitability; isogenic SOD1 correction removes it and retigabine improves mutant-cell survival." ], "what_would_cross_it": "" }, { "subclaim_id": "SC2", "threshold": "Ζ", "requirement_quoted": "Requires:\n- Multiple independent causal lines in vivo\n- Replication across at least two relevant systems\n- Narrowing of major alternative models", "satisfied": "yes", "supporting_evidence": [ "[1] Astrocytic membralin loss lowers EAAT2 and causes motor phenotypes; restoring EAAT2 or membralin protects in engineered settings.", "[5] Astrocytic YAP loss exacerbates poly-GA-model phenotypes; LDN-212320 restores EAAT2 and partially rescues motor and neuronal readouts.", "[14] AAV9-ADAR2 delivery rescues motor-neuron loss, function and TDP-43 distribution in conditional ADAR2-deficient mice.", "[15] Perampanel protects motor and neuronal readouts in AR2 mice.", "[19] ICV AMPA aptamers improve motor and neuronal readouts in AR2 mice.", "[25] Ventral astrocytes regulate strain-dependent GluR2 and motor-neuron susceptibility; mutant SOD1 disrupts this capacity.", "[26] Conditional ADAR2 loss in a cholinergic motor-neuron subset causes slow neuronal loss; endogenous edited-GluR2 replacement preserves neurons and motor function despite ADAR2 absence.", "[30] VEGF induces GluR2 and lowers AMPA calcium permeability and vulnerability in cultured neurons; ICV treatment induces ventral-spinal expression.", "[31] Mutant-SOD1 astrocytes are mGluR5-vulnerable; in vivo mGluR5 blockade slows astrocyte damage and modestly delays disease.", "[37] Chemogenetic cortical parvalbumin-interneuron activation reduces pyramidal hyperexcitability and improves onset, neuronal and survival outcomes in SOD1 mice.", "[44] Astrocytic Kir4.1 loss reduces peak strength and changes fast-motor-neuron size but is dispensable for survival even in SOD1 background.", "[57] Mutant-FUS astrocyte conditioned medium kills neurons; TNF neutralization blocks toxicity and receptor composition changes accompany it.", "[61] Hoxb8-Cre spinal GLT1 deletion produces motor deficits and motor-neuron loss.", "[66] SOD1, C9orf72 and FUS iPSC neurons show hyperexcitability; isogenic SOD1 correction removes it and retigabine improves mutant-cell survival." ], "what_would_cross_it": "" }, { "subclaim_id": "SC2", "threshold": "Η", "requirement_quoted": "Requires:\n- Strong convergent causal evidence across systems\n- Intervention-sensitive change in trajectory\n- No major unresolved contradiction about whether the mechanism is upstream versus downstream", "satisfied": "no", "supporting_evidence": [ "[1] Astrocytic membralin loss lowers EAAT2 and causes motor phenotypes; restoring EAAT2 or membralin protects in engineered settings.", "[5] Astrocytic YAP loss exacerbates poly-GA-model phenotypes; LDN-212320 restores EAAT2 and partially rescues motor and neuronal readouts.", "[14] AAV9-ADAR2 delivery rescues motor-neuron loss, function and TDP-43 distribution in conditional ADAR2-deficient mice.", "[15] Perampanel protects motor and neuronal readouts in AR2 mice.", "[19] ICV AMPA aptamers improve motor and neuronal readouts in AR2 mice.", "[25] Ventral astrocytes regulate strain-dependent GluR2 and motor-neuron susceptibility; mutant SOD1 disrupts this capacity.", "[26] Conditional ADAR2 loss in a cholinergic motor-neuron subset causes slow neuronal loss; endogenous edited-GluR2 replacement preserves neurons and motor function despite ADAR2 absence.", "[30] VEGF induces GluR2 and lowers AMPA calcium permeability and vulnerability in cultured neurons; ICV treatment induces ventral-spinal expression.", "[31] Mutant-SOD1 astrocytes are mGluR5-vulnerable; in vivo mGluR5 blockade slows astrocyte damage and modestly delays disease.", "[37] Chemogenetic cortical parvalbumin-interneuron activation reduces pyramidal hyperexcitability and improves onset, neuronal and survival outcomes in SOD1 mice.", "[44] Astrocytic Kir4.1 loss reduces peak strength and changes fast-motor-neuron size but is dispensable for survival even in SOD1 background.", "[57] Mutant-FUS astrocyte conditioned medium kills neurons; TNF neutralization blocks toxicity and receptor composition changes accompany it.", "[61] Hoxb8-Cre spinal GLT1 deletion produces motor deficits and motor-neuron loss.", "[66] SOD1, C9orf72 and FUS iPSC neurons show hyperexcitability; isogenic SOD1 correction removes it and retigabine improves mutant-cell survival." ], "what_would_cross_it": "A selective, target-engaged perturbation matching SC2 with independently measured neuronal survival and functional trajectory, stage-matched controls and replication across prespecified contexts." }, { "subclaim_id": "SC3", "threshold": "Δ", "requirement_quoted": "Requires at least one genuine causal perturbation in a disease-relevant in vivo system, or equivalent human natural experiment that materially supports the mechanism.", "satisfied": "yes", "supporting_evidence": [ "[2] EAAT2 translational activator improves motor function and survival in a mouse ALS model.", "[45] GLT1-expressing transplanted marrow-derived cells improve mouse motor behavior and survival and shift inflammatory markers.", "[60] Mouse endogenous EAAT2-D504N blocks cleavage; progression and lifespan improve modestly in SOD1-G93A mice with matched transgene-copy checks." ], "what_would_cross_it": "" }, { "subclaim_id": "SC3", "threshold": "Ε", "requirement_quoted": "Requires causal support in a defined context, but with clear restriction by subtype, disease stage, model, or tissue.\n\nUse Ε when there is a real causal contribution, but generalization to the entire disease class fails.", "satisfied": "yes", "supporting_evidence": [ "[2] EAAT2 translational activator improves motor function and survival in a mouse ALS model.", "[45] GLT1-expressing transplanted marrow-derived cells improve mouse motor behavior and survival and shift inflammatory markers.", "[60] Mouse endogenous EAAT2-D504N blocks cleavage; progression and lifespan improve modestly in SOD1-G93A mice with matched transgene-copy checks." ], "what_would_cross_it": "" }, { "subclaim_id": "SC3", "threshold": "Ζ", "requirement_quoted": "Requires:\n- Multiple independent causal lines in vivo\n- Replication across at least two relevant systems\n- Narrowing of major alternative models", "satisfied": "no", "supporting_evidence": [ "[2] EAAT2 translational activator improves motor function and survival in a mouse ALS model.", "[45] GLT1-expressing transplanted marrow-derived cells improve mouse motor behavior and survival and shift inflammatory markers.", "[60] Mouse endogenous EAAT2-D504N blocks cleavage; progression and lifespan improve modestly in SOD1-G93A mice with matched transgene-copy checks." ], "what_would_cross_it": "A selective, target-engaged perturbation matching SC3 with independently measured neuronal survival and functional trajectory, stage-matched controls and replication across prespecified contexts." }, { "subclaim_id": "SC4", "threshold": "Δ", "requirement_quoted": "Requires at least one genuine causal perturbation in a disease-relevant in vivo system, or equivalent human natural experiment that materially supports the mechanism.", "satisfied": "no", "supporting_evidence": [ "[13] The ceftriaxone phase-3 dataset contains 513 participants (340 active and 173 placebo); functional decline and survival were not significantly improved.", "[16] Perampanel randomized 66 patients and analyzed 65; only 7/21 in the 8-mg group completed 48 weeks versus 18/22 placebo. Primary mixed-model ALSFRS-R change was worse at 8 mg.", "[35] Presymptomatic mutant-SOD1 motor-neuron excitation is reduced; independent chemogenetic signaling/activity manipulation restores synapses and improves pathological readouts.", "[39] A 155-patient placebo-controlled riluzole trial found a survival advantage and slower strength deterioration.", "[42] Talampanel phase II randomized 59 ALS participants; favorable numerical strength/ALSFRS trends did not reach statistical significance.", "[43] Single-nucleus spinal profiles identify inflammatory glial states; RIPK1 blockade delays SOD1-mouse symptoms and modulates responses.", "[47] TDP-43 loss activates a UNC13A cryptic exon; ALS-risk variants increase mis-splicing and reduce protein.", "[48] Independent experiments link UNC13A risk variants to TDP-43-dependent cryptic splicing and protein depletion.", "[49] STMN2 cryptic processing is corrected by targeted reagents; axonal regeneration/lysosome trafficking recover in deficient human motor neurons.", "[50] Loss of TDP-43 reduces STMN2 through premature polyadenylation; STMN2 restoration rescues axonal regenerative capacity.", "[51] TDP-43/STMN2 perturbation and stabilization connect transcript loss to neurite and regeneration deficits.", "[52] Endogenous Stmn2 loss causes denervation and motor dysfunction; human STMN2 BAC rescues motor phenotypes.", "[53] Sarm1 deletion attenuates TDP-43-model axon/neuromuscular-junction and neuron loss, but not behavioral deficits.", "[58] Motor-neuron-derived extracellular miR-218 lowers astrocytic EAAT2; antisense inhibition mitigates changes in ALS mice.", "[59] Disrupting oligodendroglial MCT1 injures axons/neurons, and MCT1 is reduced in ALS materials.", "[67] Enhancing susceptible motor-neuron excitability/mTOR protects in SOD1 models; reducing it worsens pathology and disease.", "[69] The 959-person riluzole dose-ranging trial supports survival benefit; the prespecified 100-mg comparison differs before versus after prognostic adjustment." ], "what_would_cross_it": "A selective, target-engaged perturbation matching SC4 with independently measured neuronal survival and functional trajectory, stage-matched controls and replication across prespecified contexts." }, { "subclaim_id": "SC5", "threshold": "Δ", "requirement_quoted": "Requires at least one genuine causal perturbation in a disease-relevant in vivo system, or equivalent human natural experiment that materially supports the mechanism.", "satisfied": "no", "supporting_evidence": [ "[1] Astrocytic membralin loss lowers EAAT2 and causes motor phenotypes; restoring EAAT2 or membralin protects in engineered settings.", "[2] EAAT2 translational activator improves motor function and survival in a mouse ALS model.", "[5] Astrocytic YAP loss exacerbates poly-GA-model phenotypes; LDN-212320 restores EAAT2 and partially rescues motor and neuronal readouts.", "[13] The ceftriaxone phase-3 dataset contains 513 participants (340 active and 173 placebo); functional decline and survival were not significantly improved.", "[16] Perampanel randomized 66 patients and analyzed 65; only 7/21 in the 8-mg group completed 48 weeks versus 18/22 placebo. Primary mixed-model ALSFRS-R change was worse at 8 mg.", "[26] Conditional ADAR2 loss in a cholinergic motor-neuron subset causes slow neuronal loss; endogenous edited-GluR2 replacement preserves neurons and motor function despite ADAR2 absence.", "[31] Mutant-SOD1 astrocytes are mGluR5-vulnerable; in vivo mGluR5 blockade slows astrocyte damage and modestly delays disease.", "[35] Presymptomatic mutant-SOD1 motor-neuron excitation is reduced; independent chemogenetic signaling/activity manipulation restores synapses and improves pathological readouts.", "[37] Chemogenetic cortical parvalbumin-interneuron activation reduces pyramidal hyperexcitability and improves onset, neuronal and survival outcomes in SOD1 mice.", "[39] A 155-patient placebo-controlled riluzole trial found a survival advantage and slower strength deterioration.", "[42] Talampanel phase II randomized 59 ALS participants; favorable numerical strength/ALSFRS trends did not reach statistical significance.", "[43] Single-nucleus spinal profiles identify inflammatory glial states; RIPK1 blockade delays SOD1-mouse symptoms and modulates responses.", "[44] Astrocytic Kir4.1 loss reduces peak strength and changes fast-motor-neuron size but is dispensable for survival even in SOD1 background.", "[45] GLT1-expressing transplanted marrow-derived cells improve mouse motor behavior and survival and shift inflammatory markers.", "[47] TDP-43 loss activates a UNC13A cryptic exon; ALS-risk variants increase mis-splicing and reduce protein.", "[48] Independent experiments link UNC13A risk variants to TDP-43-dependent cryptic splicing and protein depletion.", "[49] STMN2 cryptic processing is corrected by targeted reagents; axonal regeneration/lysosome trafficking recover in deficient human motor neurons.", "[50] Loss of TDP-43 reduces STMN2 through premature polyadenylation; STMN2 restoration rescues axonal regenerative capacity.", "[51] TDP-43/STMN2 perturbation and stabilization connect transcript loss to neurite and regeneration deficits.", "[52] Endogenous Stmn2 loss causes denervation and motor dysfunction; human STMN2 BAC rescues motor phenotypes.", "[53] Sarm1 deletion attenuates TDP-43-model axon/neuromuscular-junction and neuron loss, but not behavioral deficits.", "[57] Mutant-FUS astrocyte conditioned medium kills neurons; TNF neutralization blocks toxicity and receptor composition changes accompany it.", "[58] Motor-neuron-derived extracellular miR-218 lowers astrocytic EAAT2; antisense inhibition mitigates changes in ALS mice.", "[59] Disrupting oligodendroglial MCT1 injures axons/neurons, and MCT1 is reduced in ALS materials.", "[60] Mouse endogenous EAAT2-D504N blocks cleavage; progression and lifespan improve modestly in SOD1-G93A mice with matched transgene-copy checks.", "[64] Ezogabine randomized 65 ALS participants, changes cortical/axonal excitability, and showed no significant ALSFRS-R, vital-capacity or strength effect over the short trial.", "[66] SOD1, C9orf72 and FUS iPSC neurons show hyperexcitability; isogenic SOD1 correction removes it and retigabine improves mutant-cell survival.", "[67] Enhancing susceptible motor-neuron excitability/mTOR protects in SOD1 models; reducing it worsens pathology and disease.", "[69] The 959-person riluzole dose-ranging trial supports survival benefit; the prespecified 100-mg comparison differs before versus after prognostic adjustment." ], "what_would_cross_it": "A selective, target-engaged perturbation matching SC5 with independently measured neuronal survival and functional trajectory, stage-matched controls and replication across prespecified contexts." } ], "generalization_check": { "generalization_tested": "yes", "context_boundary_mapped": "yes", "internal_negative_controls": [ "AR2 edited endogenous GluR2 rescue and Cre/flox littermates; blinded cell counts and resistant oculomotor nuclei.", "EAAT2-D504N transport/localization and non-ALS comparisons, SOD1 copy-number checks, unchanged onset and neuron counts.", "Placebo trials, trial-denominator/attrition checks, clinical versus excitability endpoints.", "Kir4.1 strength without death, opposite-direction presymptomatic excitation and non-ALS cell-role comparators." ], "note": "Tested rather than assumed: spinal versus cortical circuits, resistant versus vulnerable nuclei, developmental conditional loss versus established SOD1 insult, familial versus sporadic human ALS, acute physiology versus long-term clinical course. Contexts are specified before outcomes and no responder-defined subtype is introduced." }, "falsification_patterns_met": [ { "pattern": "Uniform hyperexcitation toxicity is contradicted in defined presymptomatic spinal motor-neuron contexts", "evidence": "PMID24094105 and32484501 report protection from increased excitation; preserved cell counts despite cleavage-resistant survival benefit in PMID28342750.", "downgrade_applied": false }, { "pattern": "Broad translational efficacy prediction fails in the examined selective AMPA trial", "evidence": "PMID34191081 primary mixed model showed worse high-dose function with major attrition; ceftriaxone PMID25297012 was clinically null without engagement.", "downgrade_applied": false } ], "pitfalls_flagged": [ { "pitfall": "Excitability biomarker treated as cell death or therapeutic benefit", "where": "Ezogabine/perampanel acute metrics versus disease endpoints." }, { "pitfall": "Species residue numbering mistaken for distinct mechanisms", "where": "Human EAAT2 D505N versus murine D504N in PMID28342750." }, { "pitfall": "Clinical negative result treated as selective mechanism falsification", "where": "Ceftriaxone exposure without spinal EAAT2 target engagement." }, { "pitfall": "Postmortem/pathway or engineered lesion generalized to human primacy", "where": "ADAR2/GLT1 sufficiency and tissue signatures versus SC4." }, { "pitfall": "Provider summary substitutions and denominator errors", "where": "Consensus omitted perampanel primary trial, supplied a 1027 ceftriaxone table count and 514 narrative; originals govern." } ], "causal_tally_audit": { "tally_claimed_by_document": 35, "tally_after_audit": 35, "items_rejected": [ "Null and negative contrasts are discriminators, not positive threshold crossings. Reports and replications are not independent causal lines.", "Shared cohorts, experimental platforms, transgenic lineages and repeated outcomes do not constitute fully independent causal lines." ] }, "steelman": { "case_one_rung_higher": "Steelman Δ: receptor-encoded rescue is unusually specific and diverse glial interventions affect disease trajectories; human physiology can appear early. The missing step is a target-engaged sporadic-human dependency test, not more correlated signatures.", "case_one_rung_lower": "Steelman Β: human signatures are mainly associative and selective trial efficacy is absent. However, endogenous lesion/rescue and progression perturbations make the mechanism more than a biomarker association within bounded motor systems.", "which_rejected": "Reject Δ for SC4 because the positive perturbations do not match sporadic-human obligate progression scope; reject Β as the nominal synthesis because experimentally discriminating mechanistic support exists. Do not apply a second downgrade for contradictions already defining the scope.", "blocking_cap_threshold_or_missing_experiment": "Missing experiment: Prospectively stratify sporadic ALS by prespecified stage and cell-specific editing/clearance status, then compare selective CP-AMPA or EAAT2 correction with a mechanistically orthogonal RNA/axonal intervention in matched human-derived systems and an adult-onset disease model before a target-engaged clinical trajectory trial." }, "final_score": { "hsef_level": "Γ", "hsef_descriptor": "Mechanistically plausible, partial system support", "confidence": "Moderate", "confidence_rationale": "69 primary reports with 6 selected partial-body examinations; density, heterogeneous controls and incomplete access set the confidence, not correctness.", "rests_on_non_peer_reviewed_work": false, "rationale": "Preregistered scope-matched SC4 returns Γ. SC2 Ζ is a bounded forced-lesion result, and SC3 Ε is a SOD1 progression result. Weakest-link sensitivity is Β from descriptive SC1, so that aggregation would mix association depth with a distinct causal-driver question." }, "role_of_mechanism": { "classification": "reinforcing / stabilizing factor", "derivation_step_matched": 5, "derivation": "For the nominal common-ALS scope the evidence supports conditional amplification and maintenance, while engineered ADAR2/GLT1 lesions can initiate their own model. EAAT2-cleavage intervention acts after onset; human biomarkers do not identify an obligate progression bottleneck.", "tournament_used_as_tiebreaker": false, "note": "Derived from causal direction, not tournament rank." }, "extended_scoring_MSD": { "momentum": { "value": "Mechanistic only", "artifact": "Recent primary perturbation work in this corpus — RIPK1 glial-state perturbation (PMID40132594), astrocytic YAP/EAAT2 rescue in the poly-GA model (PMID40860154) and targeted STMN2 processing correction (PMID36927019) — tests mechanistic and functional boundaries. No trial or programme addressing the sporadic-human dependency boundary check is named, and no presently recruiting trial is claimed.", "justification": "Recent primary perturbation work in this corpus — RIPK1 glial-state perturbation (PMID40132594), astrocytic YAP/EAAT2 rescue in the poly-GA model (PMID40860154) and targeted STMN2 processing correction (PMID36927019) — tests mechanistic and functional boundaries. No trial or programme addressing the sporadic-human dependency boundary check is named, and no presently recruiting trial is claimed." }, "stability": { "value": "Stable", "trigger": "No named pending result is asserted to be likely to move the registered score imminently.", "justification": "No named pending result is asserted to be likely to move the registered score imminently." }, "divergence": { "implied_level": null, "implied_level_basis": "No single field-implied level is defensible from conflicting framings.", "assessed_level": "Γ", "gap_in_rungs": null, "value": "Contested", "justification": "No manufactured field consensus or arithmetic gap." }, "calibration_note": "M/S/D never modify HSEF level or confidence." }, "change_record": { "applies": false, "prior_level": "Ranking categorical verdict visible; no prior letter used as a target", "prior_confidence": null, "prior_source": null, "derived_before_consulting_prior": false, "new_level": "Γ", "direction": "newly assigned", "what_moved_it": "Fresh primary evidence appraisal; not blinded.", "divergence_from_other_reviewers": null }, "proposed_decisive_experiments": [ { "name": "Registered boundary experiment", "experiment": "Prospectively stratify sporadic ALS by prespecified stage and cell-specific editing/clearance status, then compare selective CP-AMPA or EAAT2 correction with a mechanistically orthogonal RNA/axonal intervention in matched human-derived systems and an adult-onset disease model before a target-engaged clinical trajectory trial.", "readout": "Receptor/clearance engagement, neuron counts, axon/NMJ integrity, motor function and survival measured separately", "critical_control": "Edited-GluA2 versus nonediting rescue, transporter-dead control, physiological excitation preservation, isogenic comparator and blinded attrition-aware analysis", "supporting_result": "Selective correction suppresses degeneration across prespecified contexts and adds no protection when the mediator is already normalized", "falsifying_result": "Confirmed normalization leaves death/progression intact while orthogonal correction rescues it, or suppression worsens function in the proposed target context" } ], "knowledge_gaps": [ { "name": "Gap 1", "statement": "A spinal astrocytic EAAT2 pharmacodynamic assay in living patients is missing from the examined ceftriaxone trial; CSF drug concentration cannot substitute.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 2", "statement": "Human ADAR2/GluA2 editing needs prospective causal ordering before cell loss rather than selected postmortem survivors.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 3", "statement": "CP-AMPA versus broadly suppressing physiological excitation must be separated by motor pool, compartment and disease stage.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 4", "statement": "EAAT2 transport loss must be distinguished from toxic CTE-SUMO1 signaling with transport-preserving matched perturbations.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 5", "statement": "Sporadic human subtype boundaries and genotype-specific mechanisms need prespecified replication, not pooling or responder-defined explanations.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 6", "statement": "The original perampanel abstract/Table 2 confidence-interval discrepancy and attrition-dependent sensitivity require explicit retention until a publisher correction or raw-data reanalysis resolves them.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 7", "statement": "Motor strength, NMJ loss, cell counts, excitability and survival should be measured independently; one cannot substitute for another.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 8", "statement": "Controlled negative and null results need the same source-depth scrutiny as positive model rescues.", "relevance": "Limits mechanism identification or scope." } ], "review_metadata": { "review_date": "2026-10-08", "reviewer": "Codex", "evidence_base_note": "69 primary reports; literature cutoff 2026-10-08; source examination UTC date 2026-10-08; bounded critical review, not exhaustive systematic review.", "literature_tools_available": true, "literature_tools_note": "Life Sciences Literature PubMed/Entrez; attempted Europe PMC XML and successful public NCBI PMC direct HTTPS access are separately logged. Signed-in Consensus browser discovery and targeted indexed full-text checks are reconciled with original sections; failed matches and source substitutions remain explicit. Zero Consensus API calls.", "skill_version": "5.3", "validator_run": "exact archived v5.3 validator 2.3; see validator.txt", "validator_warnings_addressed": "Phenomenon entry was restated as the preregistered causal claim. No real phenomenon is labelled refuted; warning is explicitly justified.", "consensus_consistency_audit": "2026-10-09; supplementary provenance/source reconciliation; original grading retained; prior grades visible." }, "is_calibration_entry": { "value": false, "entry_role": "not_calibration", "blind_graded": null, "completed_blinded_calibration": false, "expected_band_sealed_at": "", "target_sha256": "", "target_authorship": "not applicable", "target_author_saw_review": null, "future_run_status": "not prepared", "unblinded_reason": "Ranking categorical verdict and index guidance were visible. No completed blinded calibration claimed." }, "upper_ladder_check": { "final_level_below_zeta": true, "equivalents_considered": [ { "kind": "mendelian_randomization", "available": false, "why_not_sufficient": "Human interventions were examined against functional/survival endpoints. Riluzole is not a selective glutamate-pathway instrument; ceftriaxone lacks spinal EAAT2 engagement and perampanel has null/harm with attrition. Human EAAT2 variants and postmortem editing are not validated instruments for sporadic progression. These limitations block upper rungs for the nominal scope while leaving SC2 Ζ reachable." }, { "kind": "natural_experiment", "available": false, "why_not_sufficient": "Human interventions were examined against functional/survival endpoints. Riluzole is not a selective glutamate-pathway instrument; ceftriaxone lacks spinal EAAT2 engagement and perampanel has null/harm with attrition. Human EAAT2 variants and postmortem editing are not validated instruments for sporadic progression. These limitations block upper rungs for the nominal scope while leaving SC2 Ζ reachable." }, { "kind": "dose_response_across_populations", "available": false, "why_not_sufficient": "Human interventions were examined against functional/survival endpoints. Riluzole is not a selective glutamate-pathway instrument; ceftriaxone lacks spinal EAAT2 engagement and perampanel has null/harm with attrition. Human EAAT2 variants and postmortem editing are not validated instruments for sporadic progression. These limitations block upper rungs for the nominal scope while leaving SC2 Ζ reachable." }, { "kind": "withdrawal_rechallenge", "available": false, "why_not_sufficient": "Human interventions were examined against functional/survival endpoints. Riluzole is not a selective glutamate-pathway instrument; ceftriaxone lacks spinal EAAT2 engagement and perampanel has null/harm with attrition. Human EAAT2 variants and postmortem editing are not validated instruments for sporadic progression. These limitations block upper rungs for the nominal scope while leaving SC2 Ζ reachable." }, { "kind": "therapeutic_perturbation_hard_endpoint", "available": false, "why_not_sufficient": "Human interventions were examined against functional/survival endpoints. Riluzole is not a selective glutamate-pathway instrument; ceftriaxone lacks spinal EAAT2 engagement and perampanel has null/harm with attrition. Human EAAT2 variants and postmortem editing are not validated instruments for sporadic progression. These limitations block upper rungs for the nominal scope while leaving SC2 Ζ reachable." } ], "convergence_present": true, "cap_reapplied_to_convergent_set": false }, "provenance_header": { "sources_total": 69, "claims_total": 75, "claims_verified": 75, "claims_unverified": 0, "claims_contradicted": 0, "tier_a_sources": 69, "generated_by": "Codex; HSEF v5.3", "gate_passed": true }, "claims": [ { "id": "C1", "text": "Astrocytic membralin loss lowers EAAT2 and causes motor phenotypes; restoring EAAT2 or membralin protects in engineered settings. Membralin regulates broader inflammatory pathways; forced deletion and SOD1 rescue do not establish sporadic human primacy.", "carries_number": true, "load_bearing_for": [ "SC2", "SC5" ], "source_ns": [ 1 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C2", "text": "EAAT2 translational activator improves motor function and survival in a mouse ALS model. PKC/YB1 effects and engineered background constrain attribution; clinical spinal engagement is untested.", "carries_number": true, "load_bearing_for": [ "SC3", "SC5" ], "source_ns": [ 2 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C3", "text": "EAAT2 overexpression protects cocultured motor neurons from glutamate exposure. Forced receptor milieu and transporter expression do not establish endogenous ALS necessity.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 3 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C4", "text": "An EAAT2 N206S variant detected in an ALS patient impairs transport-related properties in assays. A single detected variant is not segregation evidence or an explanation of common sporadic ALS.", "carries_number": true, "load_bearing_for": [ "SC1" ], "source_ns": [ 4 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C5", "text": "Astrocytic YAP loss exacerbates poly-GA-model phenotypes; LDN-212320 restores EAAT2 and partially rescues motor and neuronal readouts. Neonatal AAV-GA100 forces the disease insult; YAP has broad effects and neuronal Wnt induction is a protective response. This is not upstream sporadic primacy.", "carries_number": true, "load_bearing_for": [ "SC2", "SC5" ], "source_ns": [ 5 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 2:Results:paragraph0, 2:Results:paragraph2, 2:Results:paragraph8, 2:Results:paragraph9, 2:Results:paragraph13, 2:Results:paragraph14, 2:Results:paragraph15. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C6", "text": "Neuronal EAAT2 overexpression increases glutamate injury in hippocampal slice experiments. Non-ALS cell-role comparator; does not refute appropriate astrocytic transporter restoration.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 6 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C7", "text": "ALS specimens show marked EAAT2 protein and transport loss without corresponding mRNA changes. Postmortem association leaves degradation, downstream damage and reverse causation unresolved.", "carries_number": true, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 7 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C8", "text": "Forced CTE-SUMO1 expression alters astrocytes and damages cocultured motor-neuron/axon readouts. A toxic transporter fragment may act beyond clearance; cultured fragment expression is not physiological necessity.", "carries_number": true, "load_bearing_for": [ "SC3" ], "source_ns": [ 8 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C9", "text": "Platelet EAAT2 protein and uptake are not reduced in this ALS comparison. Peripheral platelets do not directly test spinal astrocyte transporter dysfunction.", "carries_number": true, "load_bearing_for": [ "SC1" ], "source_ns": [ 9 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C10", "text": "Caspase-3 cleaves EAAT2 and impairs transport; mutant-SOD1 contexts contain the truncated species. Cleavage association is not proof of disease necessity; biochemical human D505 numbering must be separated from mouse D504.", "carries_number": true, "load_bearing_for": [ "SC3" ], "source_ns": [ 10 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C11", "text": "EAAT2 splice variants occur in ALS and non-ALS tissue; tested CSF assays did not find the proposed transcripts. Specific splice-variant attribution fails; neither null CSF transcripts nor this finding excludes other transporter lesions.", "carries_number": true, "load_bearing_for": [ "SC1" ], "source_ns": [ 11 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C12", "text": "Ceftriaxone induces EAAT2 via NF-kappaB in human fetal astrocytes; RNAi removes the uptake effect. Fetal isolated cells are not adult spinal target engagement or clinical efficacy.", "carries_number": true, "load_bearing_for": [ "SC2", "SC5" ], "source_ns": [ 12 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C13", "text": "The ceftriaxone phase-3 dataset contains 513 participants (340 active and 173 placebo); functional decline and survival were not significantly improved. CSF exposure did not establish EAAT2 activation; hepatobiliary toxicity and treatment discontinuation constrain a mechanism-level negative inference. Consensus table 1027 and narrative 514 are not the final analysis denominator.", "carries_number": true, "load_bearing_for": [ "SC4", "SC5" ], "source_ns": [ 13 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 2:Results:paragraph0, 2:Results:paragraph1, 2:Results:paragraph4, 2:Results:paragraph5, 3:Discussion:paragraph7. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C14", "text": "AAV9-ADAR2 delivery rescues motor-neuron loss, function and TDP-43 distribution in conditional ADAR2-deficient mice. Restoring the gene deliberately deleted in AR2 is a matched model test, not intervention in spontaneous human ALS.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 14 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C15", "text": "Perampanel protects motor and neuronal readouts in AR2 mice. Shares the ADAR2 lesion lineage with other AR2 reports; model rescue does not establish human tolerability or benefit.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 15 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C16", "text": "Perampanel randomized 66 patients and analyzed 65; only 7/21 in the 8-mg group completed 48 weeks versus 18/22 placebo. Primary mixed-model ALSFRS-R change was worse at 8 mg. Small sample, attrition and symptomatic adverse effects limit attribution to accelerated neuronal death. Table 2 CI for the -8.4 difference is -15.0 to -1.8; abstract gives a different CI. LOCF covariance sensitivity did not retain significance.", "carries_number": true, "load_bearing_for": [ "SC4", "SC5" ], "source_ns": [ 16 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Methods:paragraph2, 1:Methods:paragraph3, 1:Methods:paragraph5, 1:Methods:paragraph8, 2:Results:paragraph0, 2:Results:paragraph6, 2:Results:paragraph8, 2:Results:paragraph27. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C17", "text": "Single-dose perampanel changes cortical motor threshold in a small ALS experiment. Acute cortical physiology is not motor-neuron survival or slowed decline; curtailed recruitment limits dose comparison.", "carries_number": false, "load_bearing_for": [ "SC1", "SC5" ], "source_ns": [ 17 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C18", "text": "Glutamate exposure causes calcium-dependent FUS/TDP-43 relocalization and GRIA2-related responses. Forced exposure permits feedback mechanisms; it does not order the initiating lesion in ALS.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 18 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C19", "text": "ICV AMPA aptamers improve motor and neuronal readouts in AR2 mice. Same conditional ADAR2 platform; no independent sporadic-human causal replication.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 19 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C20", "text": "Rat motor and dorsal-horn cultures show comparable whole-cell AMPA calcium permeability despite different vulnerability. Whole-cell averages do not exclude a toxic receptor subset, and developmental rat cells are not human ALS neurons.", "carries_number": false, "load_bearing_for": [ "SC1", "SC5" ], "source_ns": [ 20 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C21", "text": "SOD1-G93A motor neurons show presymptomatic changes in synaptic GluR1/GluR2 and CB1 distribution. Trafficking and inferred permeability are not selective receptor blockade with a disease endpoint.", "carries_number": true, "load_bearing_for": [ "SC1" ], "source_ns": [ 21 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C22", "text": "Phosphorylated TDP-43 and calpain-generated fragments resist further cleavage. Biochemical persistence does not establish that excitotoxic calcium flux caused the human disease.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 22 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C23", "text": "AMPA/kainate toxicity and apoptotic responses depend on culture composition and agonist concentration. Glial maturation and exposure alter the result; cultured toxicity cannot carry organismal primacy.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 23 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C24", "text": "Alsin deficiency alters GRIP1 and surface GluR2 and increases glutamate susceptibility. Juvenile ALS2 and receptor susceptibility are a specific context, not common sporadic disease dependency.", "carries_number": true, "load_bearing_for": [ "SC2", "SC5" ], "source_ns": [ 24 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C25", "text": "Ventral astrocytes regulate strain-dependent GluR2 and motor-neuron susceptibility; mutant SOD1 disrupts this capacity. Rat strain and mutant-protein context restrict generalization and do not isolate a universal initiating pathway.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 25 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C26", "text": "Conditional ADAR2 loss in a cholinergic motor-neuron subset causes slow neuronal loss; endogenous edited-GluR2 replacement preserves neurons and motor function despite ADAR2 absence. Developmental Cre and selective lesion define the scope; oculomotor neurons resist reduced editing. Original cell counts were blinded; rescue at six months is not a clinical sporadic-ALS test.", "carries_number": true, "load_bearing_for": [ "SC2", "SC5" ], "source_ns": [ 26 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Publisher HTML paragraphs:paragraph15, 0:Publisher HTML paragraphs:paragraph16, 0:Publisher HTML paragraphs:paragraph25, 0:Publisher HTML paragraphs:paragraph33, 0:Publisher HTML paragraphs:paragraph41, 0:Publisher HTML paragraphs:paragraph42, 0:Publisher HTML paragraphs:paragraph43, 0:Publisher HTML paragraphs:paragraph44, 0:Publisher HTML paragraphs:paragraph45. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C27", "text": "Kainate selectively kills calcium-permeable-AMPA-positive motor neurons; AMPA and receptor-subset blockade prevent cultured death. Pharmacologically forced exposure is not an ALS trajectory; GluR2 immunoreactivity does not itself imply receptor impermeability.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 27 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C28", "text": "In situ assays did not detect GluR2 mRNA in normal human spinal motor neurons and predict atypical receptor composition. Detection sensitivity and inference from transcript to assembled receptor constrain the claim; normal tissue does not establish ALS mechanism.", "carries_number": true, "load_bearing_for": [ "SC1" ], "source_ns": [ 28 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C29", "text": "Normal rat oculomotor and hypoglossal neurons have comparable GluR2 transcript/protein despite differing disease vulnerability. Cross-species negative comparator challenges simple expression explanations rather than all calcium-permeable-AMPA mechanisms.", "carries_number": true, "load_bearing_for": [ "SC1", "SC5" ], "source_ns": [ 29 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C30", "text": "VEGF induces GluR2 and lowers AMPA calcium permeability and vulnerability in cultured neurons; ICV treatment induces ventral-spinal expression. VEGF has broad effects; receptor induction in vivo is not isolated ALS survival causation.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 30 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C31", "text": "Mutant-SOD1 astrocytes are mGluR5-vulnerable; in vivo mGluR5 blockade slows astrocyte damage and modestly delays disease. Interacting astrocyte degeneration is context specific and does not prove motor-neuron AMPA primacy.", "carries_number": true, "load_bearing_for": [ "SC2", "SC5" ], "source_ns": [ 31 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C32", "text": "Calcium ionophore increases mutant-SOD1 aggregation through nitric-oxide-linked responses in a cell line. Forced calcium loading and transfected SOD1 do not identify physiological ALS ordering.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 32 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C33", "text": "Cortical hyperexcitability was found in 24 ALS patients despite preserved tested APB lower-motor-unit measures. Within-patient anatomical contrast is not pre-disease longitudinal intervention; other motor pools and occult denervation remain possible.", "carries_number": true, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 33 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C34", "text": "Embryonic/neonatal SOD1-G93A cultured motor neurons have greater intrinsic firing gain. Developmental mutant overexpression and current injection are not proof of excessive synaptic glutamate in adult ALS.", "carries_number": true, "load_bearing_for": [ "SC1" ], "source_ns": [ 34 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C35", "text": "Presymptomatic mutant-SOD1 motor-neuron excitation is reduced; independent chemogenetic signaling/activity manipulation restores synapses and improves pathological readouts. Does not refute cortical hyperexcitability or calcium toxicity in other stages; it contradicts uniform benefit from suppressing motor-neuron excitation.", "carries_number": true, "load_bearing_for": [ "SC4", "SC5" ], "source_ns": [ 35 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C36", "text": "Fifty sporadic-ALS patients show cortical hyperexcitability patterns aligned with subsequently mapped contiguous spread. Longitudinal association does not selectively manipulate glutamatergic transmission or exclude shared pathology.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 36 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C37", "text": "Chemogenetic cortical parvalbumin-interneuron activation reduces pyramidal hyperexcitability and improves onset, neuronal and survival outcomes in SOD1 mice. Cortical circuit modulation differs from spinal motor-neuron silencing; engineered disease and broad network effects limit human inference.", "carries_number": true, "load_bearing_for": [ "SC2", "SC5" ], "source_ns": [ 37 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C38", "text": "Nerve-excitability measures are abnormal in 140 ALS patients, including subgroups with normal CMAP. CMAP is an indirect and insensitive loss measure; sodium/potassium conductances are not uniquely glutamate-driven.", "carries_number": true, "load_bearing_for": [ "SC1" ], "source_ns": [ 38 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C39", "text": "A 155-patient placebo-controlled riluzole trial found a survival advantage and slower strength deterioration. Riluzole has multiple receptor/channel actions; benefit does not identify EAAT2 or AMPA as the necessary causal mediator.", "carries_number": true, "load_bearing_for": [ "SC4", "SC5" ], "source_ns": [ 39 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C40", "text": "Acute randomized crossover testing did not show a riluzole effect on assessed motor-unit parameters. Acute physiological null does not negate long-term survival benefit; abstract reports limited outcome detail.", "carries_number": false, "load_bearing_for": [ "SC1", "SC5" ], "source_ns": [ 40 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C41", "text": "ALS CSF damages cultured rat cortical neurons through an apparently glutamate-independent route; riluzole does not protect. Cross-species cultured bioassay and pleiotropic resveratrol rescue do not establish the alternative mechanism in patients.", "carries_number": false, "load_bearing_for": [ "SC4", "SC5" ], "source_ns": [ 41 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C42", "text": "Talampanel phase II randomized 59 ALS participants; favorable numerical strength/ALSFRS trends did not reach statistical significance. Small trial and sedation/dizziness constrain inference; numerical trends are not demonstrated disease modification.", "carries_number": true, "load_bearing_for": [ "SC4", "SC5" ], "source_ns": [ 42 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C43", "text": "Single-nucleus spinal profiles identify inflammatory glial states; RIPK1 blockade delays SOD1-mouse symptoms and modulates responses. Independent inflammatory pathway is a rival/convergent contributor; human secreted-marker modulation is not patient survival causation.", "carries_number": true, "load_bearing_for": [ "SC4", "SC5" ], "source_ns": [ 43 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C44", "text": "Astrocytic Kir4.1 loss reduces peak strength and changes fast-motor-neuron size but is dispensable for survival even in SOD1 background. Distinct potassium-support pathway; illustrates strength/death decoupling rather than refuting astrocytic glutamate clearance.", "carries_number": true, "load_bearing_for": [ "SC2", "SC5" ], "source_ns": [ 44 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C45", "text": "GLT1-expressing transplanted marrow-derived cells improve mouse motor behavior and survival and shift inflammatory markers. Transplantation and immune-state changes prevent clean attribution to astrocytic transporter correction alone.", "carries_number": true, "load_bearing_for": [ "SC3", "SC5" ], "source_ns": [ 45 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C46", "text": "Cell-type translational profiles place early SOD1-linked synaptic/metabolic/ER changes in motor neurons before later glial changes. SOD1 ordering is not common sporadic ordering; profiles do not directly block glutamate as a downstream contributor.", "carries_number": true, "load_bearing_for": [ "SC4", "SC5" ], "source_ns": [ 46 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C47", "text": "TDP-43 loss activates a UNC13A cryptic exon; ALS-risk variants increase mis-splicing and reduce protein. Supports a functional genetic/RNA rival, not proof that all neuronal death is independent of excitotoxicity.", "carries_number": true, "load_bearing_for": [ "SC4", "SC5" ], "source_ns": [ 47 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C48", "text": "Independent experiments link UNC13A risk variants to TDP-43-dependent cryptic splicing and protein depletion. Related human tissues and TDP-43 platforms may overlap; linked erratum PMID38890465 is recorded but details not examined.", "carries_number": true, "load_bearing_for": [ "SC4", "SC5" ], "source_ns": [ 48 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C49", "text": "STMN2 cryptic processing is corrected by targeted reagents; axonal regeneration/lysosome trafficking recover in deficient human motor neurons. Functional axon repair and engineered humanized mice are not broad clinical survival proof.", "carries_number": true, "load_bearing_for": [ "SC4", "SC5" ], "source_ns": [ 49 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C50", "text": "Loss of TDP-43 reduces STMN2 through premature polyadenylation; STMN2 restoration rescues axonal regenerative capacity. Axonal regeneration is a bounded functional endpoint, not death prevention in all ALS.", "carries_number": true, "load_bearing_for": [ "SC4", "SC5" ], "source_ns": [ 50 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C51", "text": "TDP-43/STMN2 perturbation and stabilization connect transcript loss to neurite and regeneration deficits. Shares disease pathway with other STMN2 reports; restoration is not independent clinical causality.", "carries_number": true, "load_bearing_for": [ "SC4", "SC5" ], "source_ns": [ 51 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C52", "text": "Endogenous Stmn2 loss causes denervation and motor dysfunction; human STMN2 BAC rescues motor phenotypes. Different axonal-support lesion, not selective neuron death caused by glutamate. Linked erratum PMID36480942 remains an unexamined detail.", "carries_number": true, "load_bearing_for": [ "SC4", "SC5" ], "source_ns": [ 52 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C53", "text": "Sarm1 deletion attenuates TDP-43-model axon/neuromuscular-junction and neuron loss, but not behavioral deficits. Mixed FTD-like model and sex-related viability affect scope; phenotype classes must not be collapsed.", "carries_number": true, "load_bearing_for": [ "SC4", "SC5" ], "source_ns": [ 53 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C54", "text": "AMPA stimulation preferentially loads motor-neuron mitochondria and produces sustained oxidative stress. Forced cultured challenge supports calcium/mitochondrial plausibility without endogenous disease necessity.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 54 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C55", "text": "All six ALS participants had adverse events on perampanel; four withdrew and the pilot stopped. Tiny uncontrolled tolerability study cannot estimate efficacy but challenges unqualified translational optimism.", "carries_number": false, "load_bearing_for": [ "SC4", "SC5" ], "source_ns": [ 55 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C56", "text": "A target-annotated compound screen identifies AMPA, Kv7 and D2 modulation of patient-derived motor-neuron excitability. Cell excitability screens are target-discovery evidence, not organismal neuronal rescue.", "carries_number": true, "load_bearing_for": [ "SC2", "SC5" ], "source_ns": [ 56 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C57", "text": "Mutant-FUS astrocyte conditioned medium kills neurons; TNF neutralization blocks toxicity and receptor composition changes accompany it. Tagged forced FUS and culture constrain inference; inflammatory and AMPA routes can be coupled rather than exclusive.", "carries_number": false, "load_bearing_for": [ "SC2", "SC5" ], "source_ns": [ 57 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C58", "text": "Motor-neuron-derived extracellular miR-218 lowers astrocytic EAAT2; antisense inhibition mitigates changes in ALS mice. Shows an upstream neuron-to-astrocyte feedback alternative; transporter-marker rescue is not demonstrated survival benefit in the examined abstract.", "carries_number": true, "load_bearing_for": [ "SC4", "SC5" ], "source_ns": [ 58 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C59", "text": "Disrupting oligodendroglial MCT1 injures axons/neurons, and MCT1 is reduced in ALS materials. Independent metabolic-support route; its presence does not exclude interacting glutamate stress or establish universal primacy.", "carries_number": true, "load_bearing_for": [ "SC4", "SC5" ], "source_ns": [ 59 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C60", "text": "Mouse endogenous EAAT2-D504N blocks cleavage; progression and lifespan improve modestly in SOD1-G93A mice with matched transgene-copy checks. Human plasmid D505N and mouse D504N name homologous sites. Onset and measured P150 motor-neuron counts did not change; reducing toxic CTE-SUMO1 is not uniquely restoring glutamate clearance.", "carries_number": true, "load_bearing_for": [ "SC3", "SC5" ], "source_ns": [ 60 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 2:RESULTS:paragraph1, 2:RESULTS:paragraph2, 2:RESULTS:paragraph6, 2:RESULTS:paragraph8, 2:RESULTS:paragraph9, 2:RESULTS:paragraph10, 2:RESULTS:paragraph13, 2:RESULTS:paragraph14. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C61", "text": "Hoxb8-Cre spinal GLT1 deletion produces motor deficits and motor-neuron loss. Original abstract supports sufficiency within forced spinal deletion; Methods/Results not retrieved by Consensus or local PMC. Developmental timing and matched rescue details remain unverified.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 61 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C62", "text": "ADAR2-negative ALS motor neurons contain phosphorylated cytoplasmic TDP-43 and lack normal nuclear TDP-43. Colocalization does not order the lesions; surviving postmortem cells are selected.", "carries_number": true, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 62 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C63", "text": "Matched-age/postmortem-delay specimens show selective GLT1 protein loss compared with other transporters and stable GFAP. Authors explicitly permit primary defect, downregulation or other toxicity; stable GFAP is not proof of intact astrocytic function.", "carries_number": true, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 63 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C64", "text": "Ezogabine randomized 65 ALS participants, changes cortical/axonal excitability, and showed no significant ALSFRS-R, vital-capacity or strength effect over the short trial. Only four weeks at full dose; this cannot establish durable efficacy or refute a long-term effect. Active-arm discontinuation and biomarker selection constrain generalization.", "carries_number": true, "load_bearing_for": [ "SC1", "SC5" ], "source_ns": [ 64 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Publisher HTML paragraphs:paragraph45, 0:Publisher HTML paragraphs:paragraph47, 0:Publisher HTML paragraphs:paragraph49, 0:Publisher HTML paragraphs:paragraph52, 0:Publisher HTML paragraphs:paragraph55, 0:Publisher HTML paragraphs:paragraph60, 0:Publisher HTML paragraphs:paragraph69, 0:Publisher HTML paragraphs:paragraph70, 0:Publisher HTML paragraphs:paragraph77, 0:Publisher HTML paragraphs:paragraph79. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C65", "text": "An 18-person acute crossover shows retigabine axonal-excitability effects but no riluzole effect on those metrics. Single-dose physiology cannot identify the mediator of long-term survival benefit.", "carries_number": true, "load_bearing_for": [ "SC1", "SC5" ], "source_ns": [ 65 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C66", "text": "SOD1, C9orf72 and FUS iPSC neurons show hyperexcitability; isogenic SOD1 correction removes it and retigabine improves mutant-cell survival. Genetic correction validates genotype dependence, while immature cultures and Kv7 effects do not prove common adult glutamatergic primacy.", "carries_number": true, "load_bearing_for": [ "SC2", "SC5" ], "source_ns": [ 66 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C67", "text": "Enhancing susceptible motor-neuron excitability/mTOR protects in SOD1 models; reducing it worsens pathology and disease. Stage and motor-pool dependence challenge uniform hyperexcitability toxicity, without excluding excessive calcium flux in other contexts.", "carries_number": true, "load_bearing_for": [ "SC4", "SC5" ], "source_ns": [ 67 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C68", "text": "SOD1 mice show distal denervation before axon and cell-body loss; one human autopsy has denervation with preserved-appearing neurons. Temporal compartment ordering is limited by one human case and does not test glutamate directly; distal injury is not necessarily glutamate independent.", "carries_number": true, "load_bearing_for": [ "SC4", "SC5" ], "source_ns": [ 68 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C69", "text": "The 959-person riluzole dose-ranging trial supports survival benefit; the prespecified 100-mg comparison differs before versus after prognostic adjustment. Unadjusted p=.076 versus adjusted p=.002 and no separating functional scale deserve context; a multi-action drug is not selective mechanism proof.", "carries_number": true, "load_bearing_for": [ "SC4", "SC5" ], "source_ns": [ 69 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "CSC1", "text": "Β: selective transporter loss, editing defects and excitability patterns are reproducible but spatial/postmortem associations cannot determine disease dependency.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 4, 7, 9, 11, 17, 20, 21, 28, 29, 33, 34, 36, 38, 40, 62, 63, 64, 65 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-08", "note": "" }, { "id": "CSC2", "text": "Ζ: distinct endogenous ADAR2 and spinal GLT1 lesions produce motor phenotypes; endogenous edited-GluR2 rescue in AR2 narrows the major ADAR2 off-target alternative. Membralin/EAAT2 rescue adds a different glial pathway. This scope is forced-lesion sufficiency, not spontaneous disease primacy.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 1, 3, 5, 6, 12, 14, 15, 18, 19, 22, 23, 24, 25, 26, 27, 30, 31, 32, 37, 44, 54, 56, 57, 61, 66 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-08", "note": "" }, { "id": "CSC3", "text": "Ε: endogenous caspase-resistant EAAT2 knock-in changes functional progression and survival in the defined SOD1-G93A context. 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Riluzole benefit is real but multi-action; perampanel and ceftriaxone do not supply the missing selective clinical test.", "carries_number": false, "load_bearing_for": [ "SC5" ], "source_ns": [ 1, 2, 5, 12, 13, 16, 17, 20, 24, 26, 29, 31, 35, 37, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 55, 56, 57, 58, 59, 60, 64, 65, 66, 67, 68, 69 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-08", "note": "" }, { "id": "CH", "text": "Excitotoxicity is causally damaging in defined motor-neuron models and can modify SOD1 progression; its primacy across sporadic human ALS is not established.", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 26, 60, 13, 16, 67 ], "verification": "verified", "verified_against": "Bounded synthesis of examined sources; score is adjudication.", "verified_on": "2026-10-08", "note": "" } ], "citation_ledger": [ { "n": 1, "citation": "Jiang LL, Zhu B, Zhao Y et al. 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Neurology. 2014.", "tier": "A", "kind": "rct", "pmid": "25297012", "doi": "10.1016/S1474-4422(14)70222-4", "url": "https://pubmed.ncbi.nlm.nih.gov/25297012/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID25297012", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 2:Results:paragraph0, 2:Results:paragraph1, 2:Results:paragraph4, 2:Results:paragraph5, 3:Discussion:paragraph7. No complete-paper or supplement audit claimed.", "carries_claims": [ "C13", "CSC4", "CSC5", "CH" ] }, { "n": 14, "citation": "Yamashita T, Chai HL, Teramoto S et al. Rescue of amyotrophic lateral sclerosis phenotype in a mouse model by intravenous AAV9-ADAR2 delivery to motor neurons. EMBO molecular medicine. 2013.", "tier": "A", "kind": "primary", "pmid": "24115583", "doi": "10.1002/emmm.201302935", "url": "https://pubmed.ncbi.nlm.nih.gov/24115583/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "AR2-ADAR2-platform", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C14", "CSC2" ] }, { "n": 15, "citation": "Akamatsu M, Yamashita T, Hirose N et al. The AMPA receptor antagonist perampanel robustly rescues amyotrophic lateral sclerosis (ALS) pathology in sporadic ALS model mice. 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Muscle & nerve. 2021.", "tier": "A", "kind": "rct", "pmid": "34008857", "doi": "10.1002/mus.27328", "url": "https://pubmed.ncbi.nlm.nih.gov/34008857/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID34008857", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C17", "CSC1", "CSC5" ] }, { "n": 18, "citation": "Tischbein M, Baron DM, Lin YC et al. The RNA-binding protein FUS/TLS undergoes calcium-mediated nuclear egress during excitotoxic stress and is required for GRIA2 mRNA processing. The Journal of biological chemistry. 2019.", "tier": "A", "kind": "primary", "pmid": "31092554", "doi": "10.1074/jbc.RA118.005933", "url": "https://pubmed.ncbi.nlm.nih.gov/31092554/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID31092554", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C18", "CSC2" ] }, { "n": 19, "citation": "Akamatsu M, Yamashita T, Teramoto S et al. Testing of the therapeutic efficacy and safety of AMPA receptor RNA aptamers in an ALS mouse model. Life science alliance. 2022.", "tier": "A", "kind": "primary", "pmid": "35022247", "doi": "10.26508/lsa.202101193", "url": "https://pubmed.ncbi.nlm.nih.gov/35022247/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "AR2-ADAR2-platform", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C19", "CSC2" ] }, { "n": 20, "citation": "Vandenberghe W, Robberecht W, Brorson JR et al. AMPA receptor calcium permeability, GluR2 expression, and selective motoneuron vulnerability. 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The European journal of neuroscience. 2008.", "tier": "A", "kind": "primary", "pmid": "18279310", "doi": "10.1111/j.1460-9568.2008.06041.x", "url": "https://pubmed.ncbi.nlm.nih.gov/18279310/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID18279310", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C21", "CSC1" ] }, { "n": 22, "citation": "Yamashita T, Teramoto S, Kwak S et al. Phosphorylated TDP-43 becomes resistant to cleavage by calpain: A regulatory role for phosphorylation in TDP-43 pathology of ALS/FTLD. Neuroscience research. 2016.", "tier": "A", "kind": "primary", "pmid": "26723245", "doi": "10.1016/j.neures.2015.12.006", "url": "https://pubmed.ncbi.nlm.nih.gov/26723245/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID26723245", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C22", "CSC2" ] }, { "n": 23, "citation": "De Paola M, Diana V, Bigini P et al. Morphological features and responses to AMPA receptor-mediated excitotoxicity of mouse motor neurons: comparison in purified, mixed anterior horn or motor neuron/glia cocultures. Journal of neuroscience methods. 2008.", "tier": "A", "kind": "primary", "pmid": "18282609", "doi": "10.1016/j.jneumeth.2007.12.022", "url": "https://pubmed.ncbi.nlm.nih.gov/18282609/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID18282609", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C23", "CSC2" ] }, { "n": 24, "citation": "Lai C, Xie C, McCormack SG et al. Amyotrophic lateral sclerosis 2-deficiency leads to neuronal degeneration in amyotrophic lateral sclerosis through altered AMPA receptor trafficking. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2006.", "tier": "A", "kind": "primary", "pmid": "17093100", "doi": "10.1523/JNEUROSCI.2084-06.2006", "url": "https://pubmed.ncbi.nlm.nih.gov/17093100/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID17093100", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C24", "CSC2", "CSC5" ] }, { "n": 25, "citation": "Van Damme P, Bogaert E, Dewil M et al. Astrocytes regulate GluR2 expression in motor neurons and their vulnerability to excitotoxicity. Proceedings of the National Academy of Sciences of the United States of America. 2007.", "tier": "A", "kind": "primary", "pmid": "17804792", "doi": "10.1073/pnas.0705046104", "url": "https://pubmed.ncbi.nlm.nih.gov/17804792/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID17804792", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C25", "CSC2" ] }, { "n": 26, "citation": "Hideyama T, Yamashita T, Suzuki T et al. Induced loss of ADAR2 engenders slow death of motor neurons from Q/R site-unedited GluR2. 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Biochemical and biophysical research communications. 2018.", "tier": "A", "kind": "primary", "pmid": "29458024", "doi": "10.1016/j.bbrc.2018.02.132", "url": "https://pubmed.ncbi.nlm.nih.gov/29458024/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID29458024", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C61", "CSC2" ] }, { "n": 62, "citation": "Aizawa H, Sawada J, Hideyama T et al. TDP-43 pathology in sporadic ALS occurs in motor neurons lacking the RNA editing enzyme ADAR2. Acta neuropathologica. 2010.", "tier": "A", "kind": "primary", "pmid": "20372915", "doi": "10.1007/s00401-010-0678-x", "url": "https://pubmed.ncbi.nlm.nih.gov/20372915/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID20372915", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C62", "CSC1", "CSC4" ] }, { "n": 63, "citation": "Rothstein JD, Van Kammen M, Levey AI et al. Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis. Annals of neurology. 1995.", "tier": "A", "kind": "primary", "pmid": "7611729", "doi": "10.1002/ana.410380114", "url": "https://pubmed.ncbi.nlm.nih.gov/7611729/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID7611729", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C63", "CSC1", "CSC4" ] }, { "n": 64, "citation": "Wainger BJ, Macklin EA, Vucic S et al. Effect of Ezogabine on Cortical and Spinal Motor Neuron Excitability in Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial. JAMA neurology. 2021.", "tier": "A", "kind": "rct", "pmid": "33226425", "doi": "10.1001/jamaneurol.2020.4300", "url": "https://pubmed.ncbi.nlm.nih.gov/33226425/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID33226425", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Publisher HTML paragraphs:paragraph45, 0:Publisher HTML paragraphs:paragraph47, 0:Publisher HTML paragraphs:paragraph49, 0:Publisher HTML paragraphs:paragraph52, 0:Publisher HTML paragraphs:paragraph55, 0:Publisher HTML paragraphs:paragraph60, 0:Publisher HTML paragraphs:paragraph69, 0:Publisher HTML paragraphs:paragraph70, 0:Publisher HTML paragraphs:paragraph77, 0:Publisher HTML paragraphs:paragraph79. 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Intrinsic membrane hyperexcitability of amyotrophic lateral sclerosis patient-derived motor neurons. Cell reports. 2014.", "tier": "A", "kind": "primary", "pmid": "24703839", "doi": "10.1016/j.celrep.2014.03.019", "url": "https://pubmed.ncbi.nlm.nih.gov/24703839/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID24703839", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C66", "CSC2", "CSC5" ] }, { "n": 67, "citation": "Saxena S, Roselli F, Singh K et al. Neuroprotection through excitability and mTOR required in ALS motoneurons to delay disease and extend survival. 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No complete-paper or supplement audit claimed.", "carries_claims": [ "C69", "CSC4", "CSC5" ] } ], "independence_basis": { "required": true, "lines": [ { "label": "Neuronal ADAR2 lesion with endogenous edited-receptor rescue", "sources": [ 26 ], "excludes_error": "Excludes indiscriminate ADAR2 substrate loss as sufficient explanation in the tested neuronal subset." }, { "label": "Glial spinal transporter deletion", "sources": [ 61, 1 ], "excludes_error": "Different cell role and lesion from ADAR2; does not exclude developmental or broad astrocytic confounds." }, { "label": "Endogenous cleavage-resistant mediator in SOD1 disease", "sources": [ 60 ], "excludes_error": "Maintains transporter kinetics and tests progression in a different insult; survival does not imply neuron preservation." }, { "label": "Human randomized and physiological tests", "sources": [ 13, 16, 64, 69 ], "excludes_error": "Exclude simple biomarker-to-benefit equivalence, but differ in selectivity, duration and target engagement." } ], "shared_failure_mode_checked": true, "note": "ADAR2 and spinal transporter lesions fail differently, supporting the bounded SC2 set. 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