{ "$schema_version": "5.3", "review_mode": "fresh", "claim_restatement": { "index_wording": "RNA-binding Protein Aggregation", "entry_form": "phenomenon", "gradeable_restatement": "Mislocalization and aggregation of TDP-43 and FUS is the principal causal driver of neurodegeneration across ALS-FTD through nuclear loss of function and cytoplasmic toxic gain of function.", "restatement_required": true, "split_into": [], "parent_claim": null, "scope_qualifiers": [ { "qualifier": "Protein identity, genotype, localization, endogenous dosage, species and stage specified before outcomes", "determinable_before_outcome": true, "determined_from": "Enrollment and experimental design, before results; no responder-defined scope.", "action": "retained" } ] }, "hypothesis": { "name": "RNA-binding Protein Aggregation", "central_claim": "Mislocalization and aggregation of TDP-43 and FUS is the principal causal driver of neurodegeneration across ALS-FTD through nuclear loss of function and cytoplasmic toxic gain of function.", "proposed_mechanism": "Mislocalization and aggregation of TDP-43 and FUS is the principal causal driver of neurodegeneration across ALS-FTD through nuclear loss of function and cytoplasmic toxic gain of function.", "claimed_scope": "Mislocalization and aggregation of TDP-43 and FUS is the principal causal driver of neurodegeneration across ALS-FTD through nuclear loss of function and cytoplasmic toxic gain of function.", "claimed_level": [ "progression" ], "is_conjunctive": true, "conjunctive_note": "Use the index dual-arm claim, preserving aggregate-specific toxicity as distinct from mislocalization and RNA dysfunction. Broad ALS-FTD generalization gates the nominal score; Alzheimer comorbidity is a separate comparator, not an added universal claim." }, "rubric_routing": { "primary_rubric": "01-neurodegeneration.md", "secondary_rubrics": [], "index_notes_applied": [ "Use the index dual-arm claim, preserving aggregate-specific toxicity as distinct from mislocalization and RNA dysfunction. Broad ALS-FTD generalization gates the nominal score; Alzheimer comorbidity is a separate comparator, not an added universal claim." ], "rubric_fit_note": "Exact archived v5.3 framework. Any stale index empirical framing is rechecked against primary results." }, "subclaim_matrix": { "subclaims": [ { "id": "SC1", "statement": "TDP-43 or FUS mislocalization/aggregation is prevalent in ALS-FTD tissue.", "subclaim_type": "existence", "scope": "diagnosis, genotype, cell population and disease stage", "claimed_scope": "diagnosis, genotype, cell population and disease stage", "governing_rubric": "01-neurodegeneration.md", "key_evidence_anchor": "Human neuropathology with subtype controls", "hsef_level": "Β", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Original neuropathology establishes distinct pathology classes, but prevalence alone is association and cannot assign causal function. Selected case series do not license population percentages." }, { "id": "SC2", "statement": "Nuclear TDP-43 loss causes cryptic splicing and axonal/synaptic dysfunction.", "subclaim_type": "mechanism", "scope": "endogenous TDP-43 and transcript-defined human/animal systems", "claimed_scope": "endogenous TDP-43 and transcript-defined human/animal systems", "governing_rubric": "01-neurodegeneration.md", "key_evidence_anchor": "Endogenous depletion and transcript/function rescue", "hsef_level": "Ζ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Endogenous TDP depletion, UG/splice-site engineering, RNA-binding competent rescue, human axon/synaptic correction and chimeric-repressor rescue of motor function and survival in flies/mice converge on a functional contribution. Targets are species-specific and knockout rescue does not establish sporadic initiation." }, { "id": "SC3", "statement": "Cytoplasmic RBP is toxic in vivo at physiological expression.", "subclaim_type": "sufficiency", "scope": "protein abundance and localization defined before outcomes", "claimed_scope": "protein abundance and localization defined before outcomes", "governing_rubric": "01-neurodegeneration.md", "key_evidence_anchor": "Endogenous mislocalization with abundance-matched controls", "hsef_level": "Ε", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Independent endogenous mutant-FUS lines, null comparisons, cell-restricted allele reversal and FUS lowering identify toxic gain in familial-mutant mouse contexts. Nuclear restoration and mutant removal are coupled; stage and total-dose controls matter." }, { "id": "SC4", "statement": "Macroscopic aggregation itself is the toxic species.", "subclaim_type": "mechanism", "scope": "material state separated from nuclear depletion and soluble mislocalization", "claimed_scope": "material state separated from nuclear depletion and soluble mislocalization", "governing_rubric": "01-neurodegeneration.md", "key_evidence_anchor": "Aggregation-selective inhibition/restoration retaining other functions", "hsef_level": "Γ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Biophysical and forced-assembly toxicity are plausible, but no selective macroscopic-aggregate intervention retaining soluble abundance and nuclear function establishes disease-relevant necessity. Aggregate-free degeneration and restricted protective sequestration are real discriminators." }, { "id": "SC5", "statement": "The dual-arm aggregate-driven mechanism is principal across sporadic ALS-FTD.", "subclaim_type": "generalization", "scope": "sporadic versus familial genotypes and stage", "claimed_scope": "sporadic versus familial genotypes and stage", "governing_rubric": "01-neurodegeneration.md", "key_evidence_anchor": "Selective model-independent correction with trajectory endpoints", "hsef_level": "Γ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Postmortem proteinopathy, genotype models and rescues support plausible interacting pathways. No selective model-independent correction establishes this principal aggregate-driven dual mechanism across prespecified sporadic ALS–FTD contexts." } ], "aggregation_rule": "scope-matched", "aggregation_preregistered": true, "aggregation_rationale": "Use the index dual-arm claim, preserving aggregate-specific toxicity as distinct from mislocalization and RNA dysfunction. Broad ALS-FTD generalization gates the nominal score; Alzheimer comorbidity is a separate comparator, not an added universal claim.", "primary_subclaim_id": "SC5", "aggregation_derivation": "The preregistered scope-matched gate SC5 is Γ. Nuclear splicing failure has convergent causal and functional rescue evidence (SC2 Ζ), and physiological mutant-FUS toxicity is context-valid (SC3 Ε). Neither establishes selective macroscopic-aggregate toxicity or principal dual-arm causation across sporadic ALS–FTD. No narrow success silently replaces that broad gate.", "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": "Nuclear RNA dysfunction as a causal contributor", "core_claim": "Loss of specific RNA-processing functions damages neuronal maintenance.", "explains_what_nominal_does_not": "Loss of specific RNA-processing functions damages neuronal maintenance.", "strongest_supporting_evidence": [ "UG and splice-site edits, human functional correction and fly/mouse splicing-repressor trajectory rescue (PMID26250685,36927019,31332509)." ], "strongest_contradictory_evidence": [ "The rank and Ζ apply to contribution in tested contexts, not principal initiation across all sporadic disease." ], "hsef_level_for_this_model": "Ζ", "rationale": "UG and splice-site edits, human functional correction and fly/mouse splicing-repressor trajectory rescue (PMID26250685,36927019,31332509). The rank and Ζ apply to contribution in tested contexts, not principal initiation across all sporadic disease." }, { "rank_in_tournament": 2, "model_id": "M3", "is_nominal": false, "name": "Mislocalized soluble mutant-RBP toxicity", "core_claim": "Physiological mutant FUS can damage neurons before visible aggregates.", "explains_what_nominal_does_not": "Physiological mutant FUS can damage neurons before visible aggregates.", "strongest_supporting_evidence": [ "Endogenous dosage and null/allele-reversal contrasts (PMID29053787,26951610,35075293)." ], "strongest_contradictory_evidence": [ "Small assemblies are not excluded and restoring WT simultaneously repairs nuclear function." ], "hsef_level_for_this_model": "Ε", "rationale": "Endogenous dosage and null/allele-reversal contrasts (PMID29053787,26951610,35075293). Small assemblies are not excluded and restoring WT simultaneously repairs nuclear function." }, { "rank_in_tournament": 3, "model_id": "M5", "is_nominal": false, "name": "RNA/chaperone homeostatic failure", "core_claim": "RNA concentration and import/chaperone systems govern material state and localization.", "explains_what_nominal_does_not": "RNA concentration and import/chaperone systems govern material state and localization.", "strongest_supporting_evidence": [ "RNA buffering, HSP70/HSPB1 and import-receptor interventions (PMID29650702,33335017,36075972,29677512)." ], "strongest_contradictory_evidence": [ "Disease-initiation necessity is not selectively isolated; broad chaperone/import effects and forced stress remain." ], "hsef_level_for_this_model": "Γ", "rationale": "RNA buffering, HSP70/HSPB1 and import-receptor interventions (PMID29650702,33335017,36075972,29677512). Disease-initiation necessity is not selectively isolated; broad chaperone/import effects and forced stress remain." }, { "rank_in_tournament": 4, "model_id": "M1", "is_nominal": true, "name": "Principal dual-arm aggregate mechanism", "core_claim": "Nuclear loss and cytoplasmic aggregation can reinforce each other.", "explains_what_nominal_does_not": "Nuclear loss and cytoplasmic aggregation can reinforce each other.", "strongest_supporting_evidence": [ "Genetics, pathology and coupled transgene suppression support serious plausibility (PMID17023659,26197969)." ], "strongest_contradictory_evidence": [ "Physiological aggregate-free disease and incomplete organismal rescue prevent a universal principal aggregate conclusion." ], "hsef_level_for_this_model": "Γ", "rationale": "Genetics, pathology and coupled transgene suppression support serious plausibility (PMID17023659,26197969). Physiological aggregate-free disease and incomplete organismal rescue prevent a universal principal aggregate conclusion." }, { "rank_in_tournament": 5, "model_id": "M4", "is_nominal": false, "name": "Aggregates as sequestration or quality control", "core_claim": "Large assemblies can sequester more toxic soluble or liquid species.", "explains_what_nominal_does_not": "Large assemblies can sequester more toxic soluble or liquid species.", "strongest_supporting_evidence": [ "Yeast scanning and fly-eye sequestration discriminate material states (PMID31519910,25088712)." ], "strongest_contradictory_evidence": [ "Restricted artificial models do not prove protection of native human disease inclusions." ], "hsef_level_for_this_model": "Γ", "rationale": "Yeast scanning and fly-eye sequestration discriminate material states (PMID31519910,25088712). Restricted artificial models do not prove protection of native human disease inclusions." } ], "tournament_summary": "Descriptive comparison; does not modify the nominal score. Donde selective splicing-repressor rescue contrasts with Devoy physiological aggregate-free FUS degeneration: these support different causal routes, so the winner is the scoped RNA-function contributor rather than a single ALS–FTD origin (PMID31332509,29053787).", "study_separating_rank1_from_rank2": "Donde selective splicing-repressor rescue contrasts with Devoy physiological aggregate-free FUS degeneration: these support different causal routes, so the winner is the scoped RNA-function contributor rather than a single ALS–FTD origin (PMID31332509,29053787).", "nominal_wins_only_by_funding_artifact": false, "level_unchanged_by_tournament": true }, "evidence_inventory": [ { "n": 1, "pmid": "26250685", "title": "TDP-43 repression of nonconserved cryptic exons is compromised in ALS-FTD.", "citation": "Ling JP, Pletnikova O, Troncoso JC et al. TDP-43 repression of nonconserved cryptic exons is compromised in ALS-FTD. Science (New York, N.Y.). 2015.", "doi": "10.1126/science.aab0983", "pmcid": "PMC4825810", "url": "https://pubmed.ncbi.nlm.nih.gov/26250685/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26250685/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID26250685", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Main text:paragraph4, 1:Main text:paragraph5, 1:Main text:paragraph6, 1:Main text:paragraph7, 1:Main text:paragraph8, 1:Main text:paragraph9, 1:Main text:paragraph10, 1:Main text:paragraph11, 1:Main text:paragraph12, 1:Main text. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "mouse stem cells and human tissues", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "UG-dependent cryptic splicing and chimeric repressor cell-survival rescue.", "what_it_does_not_show": "Whole-body disease not tested; human mouse target sequences differ.", "confounders_present": [ "Whole-body disease not tested; human mouse target sequences differ." ], "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": [ "Ling/Donde chimeric-repressor programme shared." ] }, { "n": 2, "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": [ "Erratum in: PMID 38890465" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID35197628", "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": "human neurons genetics and tissue", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "UNC13A risk variants potentiate TDP-dependent cryptic splicing and protein loss.", "what_it_does_not_show": "Natural risk is conditional; erratum38890465 details unaudited.", "confounders_present": [ "Natural risk is conditional; erratum38890465 details unaudited." ], "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": "38277467", "title": "Mis-spliced transcripts generate de novo proteins in TDP-43-related ALS/FTD.", "citation": "Seddighi S, Qi YA, Brown AL et al. Mis-spliced transcripts generate de novo proteins in TDP-43-related ALS/FTD. Science translational medicine. 2024.", "doi": "10.1126/scitranslmed.adg7162", "pmcid": "PMC11325748", "url": "https://pubmed.ncbi.nlm.nih.gov/38277467/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38277467/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "Update of: PMID 36747793" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID38277467", "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 neurons and CSF", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Cryptic transcripts yield detectable novel peptides including CSF signals.", "what_it_does_not_show": "Peptide presence does not prove toxicity or initiating causality.", "confounders_present": [ "Peptide presence does not prove toxicity or initiating 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": 4, "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": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID36927019", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:A GU-motif confers TDP-43 binding-dependent maturation of stathmin-2 pre-mRNA, 1:TDP-43 binding sterically blocks cryptic splicing and polyadenylation of STMN2, 2:Genomic disruption of exon 2a cryptic splice site protects against misprocessing, 6:rASOs restore axonal regeneration capacity in TDP-43 deficient motor neurons, 7:rASO-mediated restoration of Stmn2 pre-mRNA processing in the mammalian CNS. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "human motor neurons and humanized mouse", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Endogenous splice-site edits and ASOs restore STMN2 and human axon regeneration.", "what_it_does_not_show": "Mouse target engagement is not disease-course rescue; regenerated injury axons are restricted endpoints.", "confounders_present": [ "Mouse target engagement is not disease-course rescue; regenerated injury axons are restricted endpoints." ], "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": "38278991", "title": "A fluid biomarker reveals loss of TDP-43 splicing repression in presymptomatic ALS-FTD.", "citation": "Irwin KE, Jasin P, Braunstein KE et al. A fluid biomarker reveals loss of TDP-43 splicing repression in presymptomatic ALS-FTD. Nature medicine. 2024.", "doi": "10.1038/s41591-023-02788-5", "pmcid": "PMC10878965", "url": "https://pubmed.ncbi.nlm.nih.gov/38278991/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38278991/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "Update of: PMID 36789434", "Erratum in: PMID 38580817" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID38278991", "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", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "presymptomatic C9 CSF", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Cryptic HDGFL2 biomarker can precede neurofilament rise.", "what_it_does_not_show": "Temporal biomarker not causal intervention; erratum38580817 details unaudited.", "confounders_present": [ "Temporal biomarker not causal intervention; erratum38580817 details unaudited." ], "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": "32790644", "title": "Truncated stathmin-2 is a marker of TDP-43 pathology in frontotemporal dementia.", "citation": "Prudencio M, Humphrey J, Pickles S et al. Truncated stathmin-2 is a marker of TDP-43 pathology in frontotemporal dementia. The Journal of clinical investigation. 2020.", "doi": "10.1172/JCI139741", "pmcid": "PMC7598060", "url": "https://pubmed.ncbi.nlm.nih.gov/32790644/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32790644/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID32790644", "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", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "FTD tissues and cells", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Truncated STMN2 tracks FTLD-TDP rather than FTLD-tau.", "what_it_does_not_show": "Postmortem association and variant-specific nuclear dysfunction.", "confounders_present": [ "Postmortem association and variant-specific nuclear 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": 7, "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": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID35197626", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Main:paragraph2, 0:Main:paragraph5, 0:Main:paragraph6, 0:Main:paragraph18, 0:Main:paragraph19, 0:Main:paragraph20, 0:Main:paragraph21. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "human tissue iPSC and reporters", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "TDP depletion reduces UNC13A; risk haplotypes amplify cryptic exon use and RNA-binding competent rescue.", "what_it_does_not_show": "Human survival association not randomized rescue; binding assay differs from companion Brown paper.", "confounders_present": [ "Human survival association not randomized rescue; binding assay differs from companion Brown paper." ], "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": "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": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID30643292", "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": "human neurons", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "STMN2 loss follows TDP depletion; stabilization restores axonal regeneration.", "what_it_does_not_show": "Injury regeneration in culture is not ALS survival.", "confounders_present": [ "Injury regeneration in culture is not ALS survival." ], "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": [ "Parallel STMN2 discovery; later target/rescue programmes reuse biology and assay families." ] }, { "n": 9, "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": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID30643298", "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": "human motor neurons", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "STMN2 correction restores axon regeneration after nuclear TDP dysfunction.", "what_it_does_not_show": "Shared target and culture challenge; disease trajectory untested.", "confounders_present": [ "Shared target and culture challenge; disease trajectory 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": [ "Parallel STMN2 discovery; later target/rescue programmes reuse biology and assay families." ] }, { "n": 10, "pmid": "38443601", "title": "RNA aptamer reveals nuclear TDP-43 pathology is an early aggregation event that coincides with STMN-2 cryptic splicing and precedes clinical manifestation in ALS.", "citation": "Spence H, Waldron FM, Saleeb RS et al. RNA aptamer reveals nuclear TDP-43 pathology is an early aggregation event that coincides with STMN-2 cryptic splicing and precedes clinical manifestation in ALS. Acta neuropathologica. 2024.", "doi": "10.1007/s00401-024-02705-1", "pmcid": "PMC10914926", "url": "https://pubmed.ncbi.nlm.nih.gov/38443601/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38443601/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID38443601", "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", "SC2", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human postmortem spatial staging", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Nuclear TDP abnormalities and cryptic splicing map to earlier regional stages than cytoplasmic burden.", "what_it_does_not_show": "Inferred timing from tissue is not longitudinal causal tracking; matched journal replaces preprint.", "confounders_present": [ "Inferred timing from tissue is not longitudinal causal tracking; matched journal replaces preprint." ], "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": "38941189", "title": "Stress-induced TDP-43 nuclear condensation causes splicing loss of function and STMN2 depletion.", "citation": "Huang WP, Ellis BCS, Hodgson RE et al. Stress-induced TDP-43 nuclear condensation causes splicing loss of function and STMN2 depletion. Cell reports. 2024.", "doi": "10.1016/j.celrep.2024.114421", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/38941189/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38941189/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID38941189", "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", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "stressed neuronal cells", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "RNA-depleted nuclear condensates accompany persistent STMN2 splicing loss.", "what_it_does_not_show": "Forced stress and coupled state-function changes do not identify sporadic initiation.", "confounders_present": [ "Forced stress and coupled state-function changes do not identify sporadic initiation." ], "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": "35767949", "title": "Loss of Stathmin-2, a hallmark of TDP-43-associated ALS, causes motor neuropathy.", "citation": "Krus KL, Strickland A, Yamada Y et al. Loss of Stathmin-2, a hallmark of TDP-43-associated ALS, causes motor neuropathy. Cell reports. 2022.", "doi": "10.1016/j.celrep.2022.111001", "pmcid": "PMC9327139", "url": "https://pubmed.ncbi.nlm.nih.gov/35767949/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35767949/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID35767949", "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": "Stmn2 conditional knockout mice", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "STMN2 is needed for motor-unit maintenance; knockout denervates fast-fatigable NMJs.", "what_it_does_not_show": "No motor-neuron or axon degeneration in this model; not full ALS phenocopy.", "confounders_present": [ "No motor-neuron or axon degeneration in this model; not full ALS phenocopy." ], "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": "27348499", "title": "The inhibition of TDP-43 mitochondrial localization blocks its neuronal toxicity.", "citation": "Wang W, Wang L, Lu J et al. The inhibition of TDP-43 mitochondrial localization blocks its neuronal toxicity. Nature medicine. 2016.", "doi": "10.1038/nm.4130", "pmcid": "PMC4974139", "url": "https://pubmed.ncbi.nlm.nih.gov/27348499/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27348499/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID27348499", "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": "TDP transgenic mice", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Blocking mitochondrial TDP import rescues neuronal and behavioral phenotypes.", "what_it_does_not_show": "Overexpression and broad mitochondrial intervention do not isolate macroscopic aggregates.", "confounders_present": [ "Overexpression and broad mitochondrial intervention do not isolate macroscopic aggregates." ], "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": "30826182", "title": "RNA Binding Antagonizes Neurotoxic Phase Transitions of TDP-43.", "citation": "Mann JR, Gleixner AM, Mauna JC et al. RNA Binding Antagonizes Neurotoxic Phase Transitions of TDP-43. Neuron. 2019.", "doi": "10.1016/j.neuron.2019.01.048", "pmcid": "PMC6472983", "url": "https://pubmed.ncbi.nlm.nih.gov/30826182/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30826182/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID30826182", "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", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "optogenetic TDP cells", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Forced cytoplasmic assemblies are toxic and RNA antagonism reduces inclusion/toxicity.", "what_it_does_not_show": "Optogenetic assembly and coupled effects cap endogenous necessity inference.", "confounders_present": [ "Optogenetic assembly and coupled effects cap endogenous necessity 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": 15, "pmid": "26197969", "title": "Functional recovery in new mouse models of ALS/FTLD after clearance of pathological cytoplasmic TDP-43.", "citation": "Walker AK, Spiller KJ, Ge G et al. Functional recovery in new mouse models of ALS/FTLD after clearance of pathological cytoplasmic TDP-43. Acta neuropathologica. 2015.", "doi": "10.1007/s00401-015-1460-x", "pmcid": "PMC5127391", "url": "https://pubmed.ncbi.nlm.nih.gov/26197969/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26197969/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID26197969", "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", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "inducible TDP transgenic mice", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Transgene suppression improves motor course and survival with restoration of nuclear TDP.", "what_it_does_not_show": "Both arms and total protein change together; overexpression model.", "confounders_present": [ "Both arms and total protein change together; overexpression model." ], "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": "28405022", "title": "Therapeutic reduction of ataxin-2 extends lifespan and reduces pathology in TDP-43 mice.", "citation": "Becker LA, Huang B, Bieri G et al. Therapeutic reduction of ataxin-2 extends lifespan and reduces pathology in TDP-43 mice. Nature. 2017.", "doi": "10.1038/nature22038", "pmcid": "PMC5642042", "url": "https://pubmed.ncbi.nlm.nih.gov/28405022/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28405022/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID28405022", "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": "TDP transgenic mice", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Ataxin2 deletion or ASO extends survival and lowers pathology.", "what_it_does_not_show": "Pleiotropic change does not selectively identify aggregate toxicity.", "confounders_present": [ "Pleiotropic change does not selectively identify aggregate toxicity." ], "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": "41174170", "title": "TDP-43-dependent mis-splicing of KCNQ2 triggers intrinsic neuronal hyperexcitability in ALS/FTD.", "citation": "Joseph BJ, Marshall KA, Harley P et al. TDP-43-dependent mis-splicing of KCNQ2 triggers intrinsic neuronal hyperexcitability in ALS/FTD. Nature neuroscience. 2025.", "doi": "10.1038/s41593-025-02096-w", "pmcid": "PMC12672377", "url": "https://pubmed.ncbi.nlm.nih.gov/41174170/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/41174170/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID41174170", "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": "human neurons", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "KCNQ2 cryptic exon produces ER-associated protein and hyperexcitability corrected by ASO.", "what_it_does_not_show": "Cell-function rescue not organismal or clinical rescue.", "confounders_present": [ "Cell-function rescue not organismal or clinical 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": 18, "pmid": "41120751", "title": "TDP-43 loss induces cryptic polyadenylation in ALS/FTD.", "citation": "Bryce-Smith S, Brown AL, Chien MZYJ et al. TDP-43 loss induces cryptic polyadenylation in ALS/FTD. Nature neuroscience. 2025.", "doi": "10.1038/s41593-025-02050-w", "pmcid": "PMC12586162", "url": "https://pubmed.ncbi.nlm.nih.gov/41120751/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/41120751/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "Update of: PMID 38313254" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID41120751", "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": "human RNA studies", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "TDP loss alters cryptic polyadenylation with both stability-increasing and decreasing effects.", "what_it_does_not_show": "Not all aberrant RNAs undergo NMD or cause neuronal death.", "confounders_present": [ "Not all aberrant RNAs undergo NMD or cause neuronal death." ], "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": "34321318", "title": "Nuclear accumulation of CHMP7 initiates nuclear pore complex injury and subsequent TDP-43 dysfunction in sporadic and familial ALS.", "citation": "Coyne AN, Baskerville V, Zaepfel BL et al. Nuclear accumulation of CHMP7 initiates nuclear pore complex injury and subsequent TDP-43 dysfunction in sporadic and familial ALS. Science translational medicine. 2021.", "doi": "10.1126/scitranslmed.abe1923", "pmcid": "PMC9022198", "url": "https://pubmed.ncbi.nlm.nih.gov/34321318/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34321318/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID34321318", "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": "ALS iPSC neurons", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "CHMP7 lowering restores pore/Ran/RNA defects and protects against glutamate challenge.", "what_it_does_not_show": "Upstream transport perturbation and challenge survival not spontaneous disease course.", "confounders_present": [ "Upstream transport perturbation and challenge survival not spontaneous disease course." ], "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": "29677512", "title": "Nuclear-Import Receptors Reverse Aberrant Phase Transitions of RNA-Binding Proteins with Prion-like Domains.", "citation": "Guo L, Kim HJ, Wang H et al. Nuclear-Import Receptors Reverse Aberrant Phase Transitions of RNA-Binding Proteins with Prion-like Domains. Cell. 2018.", "doi": "10.1016/j.cell.2018.03.002", "pmcid": "PMC5911940", "url": "https://pubmed.ncbi.nlm.nih.gov/29677512/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29677512/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID29677512", "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": "cells and in vivo RBP models", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Nuclear import receptors counter phase transitions and rescue functional or degenerative outcomes.", "what_it_does_not_show": "Import and chaperoning change together across forced models.", "confounders_present": [ "Import and chaperoning change together across forced models." ], "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": "29677514", "title": "Phase Separation of FUS Is Suppressed by Its Nuclear Import Receptor and Arginine Methylation.", "citation": "Hofweber M, Hutten S, Bourgeois B et al. Phase Separation of FUS Is Suppressed by Its Nuclear Import Receptor and Arginine Methylation. Cell. 2018.", "doi": "10.1016/j.cell.2018.03.004", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/29677514/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29677514/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID29677514", "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", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "FUS biophysics and cells", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Transportin and arginine methylation regulate FUS condensation and localization.", "what_it_does_not_show": "Material-state mechanism does not establish clinical primary cause.", "confounders_present": [ "Material-state mechanism does not establish clinical primary cause." ], "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": "28817800", "title": "TIA1 Mutations in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Promote Phase Separation and Alter Stress Granule Dynamics.", "citation": "Mackenzie IR, Nicholson AM, Sarkar M et al. TIA1 Mutations in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Promote Phase Separation and Alter Stress Granule Dynamics. Neuron. 2017.", "doi": "10.1016/j.neuron.2017.07.025", "pmcid": "PMC5576574", "url": "https://pubmed.ncbi.nlm.nih.gov/28817800/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28817800/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID28817800", "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", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "familial genetics and stress-granule cells", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "TIA1 variants link altered granule dynamics to selected ALS/FTD families.", "what_it_does_not_show": "Familial association and engineered stress cannot generalize across sporadic disease.", "confounders_present": [ "Familial association and engineered stress cannot generalize across sporadic 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": "31272829", "title": "Small-Molecule Modulation of TDP-43 Recruitment to Stress Granules Prevents Persistent TDP-43 Accumulation in ALS/FTD.", "citation": "Fang MY, Markmiller S, Vu AQ et al. Small-Molecule Modulation of TDP-43 Recruitment to Stress Granules Prevents Persistent TDP-43 Accumulation in ALS/FTD. Neuron. 2019.", "doi": "10.1016/j.neuron.2019.05.048", "pmcid": "PMC6728177", "url": "https://pubmed.ncbi.nlm.nih.gov/31272829/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31272829/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID31272829", "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", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human iPSC cell screens", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Small molecules modify stress-granule composition and TDP puncta.", "what_it_does_not_show": "Puncta reduction lacks organismal trajectory endpoint.", "confounders_present": [ "Puncta reduction lacks organismal trajectory 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": 24, "pmid": "35075293", "title": "Antisense oligonucleotide silencing of FUS expression as a therapeutic approach in amyotrophic lateral sclerosis.", "citation": "Korben VA, Lyashchenko AK, Blanco-Redondo B et al. Antisense oligonucleotide silencing of FUS expression as a therapeutic approach in amyotrophic lateral sclerosis. Nature medicine. 2022.", "doi": "10.1038/s41591-021-01615-z", "pmcid": "PMC8799464", "url": "https://pubmed.ncbi.nlm.nih.gov/35075293/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35075293/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID35075293", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph3, 1:Results:paragraph36, 1:Results:paragraph49, 1:Results:paragraph52, 1:Results:paragraph53, 1:Results:paragraph59. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "endogenous FUS knock-in mice and one patient", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Dose and conditional FUS contrasts identify mutant toxicity; P1 ION363 prevents motor-neuron loss and denervation while active.", "what_it_does_not_show": "No overt motor phenotype in initial heterozygotes; prophylactic lowering changes soluble and insoluble FUS; one patient cannot establish efficacy.", "confounders_present": [ "No overt motor phenotype in initial heterozygotes; prophylactic lowering changes soluble and insoluble FUS; one patient cannot establish 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": [ "Jacifusen single treated patient reappears in expanded-access series." ] }, { "n": 25, "pmid": "34880495", "title": "Structure of pathological TDP-43 filaments from ALS with FTLD.", "citation": "Arseni D, Hasegawa M, Murzin AG et al. Structure of pathological TDP-43 filaments from ALS with FTLD. Nature. 2022.", "doi": "10.1038/s41586-021-04199-3", "pmcid": "PMC7612255", "url": "https://pubmed.ncbi.nlm.nih.gov/34880495/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34880495/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID34880495", "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": "two human brain filament structures", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Disease filaments have structures distinct from reconstructed in vitro fibrils.", "what_it_does_not_show": "Structural identity is not toxicity or necessity.", "confounders_present": [ "Structural identity is not toxicity or 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": 26, "pmid": "32132204", "title": "TDP-43 α-helical structure tunes liquid-liquid phase separation and function.", "citation": "Conicella AE, Dignon GL, Zerze GH et al. TDP-43 α-helical structure tunes liquid-liquid phase separation and function. Proceedings of the National Academy of Sciences of the United States of America. 2020.", "doi": "10.1073/pnas.1912055117", "pmcid": "PMC7084079", "url": "https://pubmed.ncbi.nlm.nih.gov/32132204/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32132204/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID32132204", "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", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "TDP variants and minigenes", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Helical changes can enhance phase separation and splicing function.", "what_it_does_not_show": "Condensation is not intrinsically pathogenic; reporter endpoints.", "confounders_present": [ "Condensation is not intrinsically pathogenic; reporter endpoints." ], "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": "17084815", "title": "TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis.", "citation": "Arai T, Hasegawa M, Akiyama H et al. TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochemical and biophysical research communications. 2006.", "doi": "10.1016/j.bbrc.2006.10.093", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/17084815/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/17084815/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID17084815", "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": "ALS/FTD neuropathology", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "TDP protein identified in selected disease inclusions.", "what_it_does_not_show": "Postmortem presence cannot assign cause.", "confounders_present": [ "Postmortem presence cannot assign cause." ], "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": "40913764", "title": "A single-cell, long-read, isoform-resolved case-control study of FTD reveals cell-type-specific and broad splicing dysregulation in human brain.", "citation": "Belchikov N, Hu W, Fan L et al. A single-cell, long-read, isoform-resolved case-control study of FTD reveals cell-type-specific and broad splicing dysregulation in human brain. Cell reports. 2025.", "doi": "10.1016/j.celrep.2025.116198", "pmcid": "PMC12558363", "url": "https://pubmed.ncbi.nlm.nih.gov/40913764/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40913764/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID40913764", "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": "GRN-FTD single-nucleus long reads", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Cell-layer analysis exposes splicing defects masked by bulk RNA.", "what_it_does_not_show": "Defined genetic FTD subset and observational tissue.", "confounders_present": [ "Defined genetic FTD subset and observational tissue." ], "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": "21052700", "title": "Distinct pathological subtypes of FTLD-FUS.", "citation": "Mackenzie IR, Munoz DG, Kusaka H et al. Distinct pathological subtypes of FTLD-FUS. Acta neuropathologica. 2011.", "doi": "10.1007/s00401-010-0764-0", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/21052700/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/21052700/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID21052700", "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": "23 FTLD-FUS cases", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Distinct FUS-positive TDP/tau-negative subtypes constrain a uniform protein account.", "what_it_does_not_show": "Selected case series cannot estimate all-population prevalence.", "confounders_present": [ "Selected case series cannot estimate all-population prevalence." ], "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": "37996528", "title": "Stathmin-2 loss leads to neurofilament-dependent axonal collapse driving motor and sensory denervation.", "citation": "López-Erauskin J, Bravo-Hernandez M, Presa M et al. Stathmin-2 loss leads to neurofilament-dependent axonal collapse driving motor and sensory denervation. Nature neuroscience. 2024.", "doi": "10.1038/s41593-023-01496-0", "pmcid": "PMC10842032", "url": "https://pubmed.ncbi.nlm.nih.gov/37996528/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37996528/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID37996528", "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": "adult Stmn2 depletion and knockout mice", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "STMN2 loss alters axon caliber conduction denervation and motor behavior.", "what_it_does_not_show": "Not selective rescue of endogenous sporadic TDP disease.", "confounders_present": [ "Not selective rescue of endogenous sporadic TDP 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": 31, "pmid": "42234776", "title": "Cryptic splicing in synaptic and membrane excitability genes links TDP-43 loss to neuronal dysfunction.", "citation": "Guo C, Chen K, Vatsavayai S et al. Cryptic splicing in synaptic and membrane excitability genes links TDP-43 loss to neuronal dysfunction. Science translational medicine. 2026.", "doi": "10.1126/scitranslmed.aeb8517", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/42234776/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/42234776/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "Update of: PMID 40949955" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID42234776", "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": "human stem-cell neurons", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Combined correction of KALRN RAP1GAP SYT7 KCNQ2 nearly restores synaptic function after TDP loss.", "what_it_does_not_show": "Multitarget culture rescue not systemic survival; journal report deduplicated from preprint.", "confounders_present": [ "Multitarget culture rescue not systemic survival; journal report deduplicated from preprint." ], "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": "17023659", "title": "Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis.", "citation": "Neumann M, Sampathu DM, Kwong LK et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science (New York, N.Y.). 2006.", "doi": "10.1126/science.1134108", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/17023659/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/17023659/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID17023659", "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 ALS/FTLD pathology", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Modified ubiquitinated TDP defines a shared pathology class.", "what_it_does_not_show": "End-stage association does not resolve toxic species.", "confounders_present": [ "End-stage association does not resolve toxic species." ], "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": "18309045", "title": "TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis.", "citation": "Sreedharan J, Blair IP, Tripathi VB et al. TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science (New York, N.Y.). 2008.", "doi": "10.1126/science.1154584", "pmcid": "PMC7116650", "url": "https://pubmed.ncbi.nlm.nih.gov/18309045/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/18309045/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID18309045", "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": "TARDBP families and chick development", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Segregating variants support gene-level etiology; engineered developmental toxicity.", "what_it_does_not_show": "Gene causality does not prove aggregates or all sporadic mechanism.", "confounders_present": [ "Gene causality does not prove aggregates or all sporadic 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": 34, "pmid": "19251628", "title": "Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6.", "citation": "Vance C, Rogelj B, Hortobágyi T et al. Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science (New York, N.Y.). 2009.", "doi": "10.1126/science.1165942", "pmcid": "PMC4516382", "url": "https://pubmed.ncbi.nlm.nih.gov/19251628/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/19251628/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID19251628", "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": "FUS families and postmortem cases", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "FUS mutations segregate in defined ALS families with abnormal localization.", "what_it_does_not_show": "Familial etiology is not universal sporadic mechanism.", "confounders_present": [ "Familial etiology is not universal sporadic 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": 35, "pmid": "19251627", "title": "Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis.", "citation": "Kwiatkowski TJ, Bosco DA, Leclerc AL et al. Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science (New York, N.Y.). 2009.", "doi": "10.1126/science.1166066", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/19251627/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/19251627/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID19251627", "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": "familial FUS genetics", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Multiple familial mutations alter FUS localization.", "what_it_does_not_show": "Localization and gene effects remain coupled; no aggregate-selective intervention.", "confounders_present": [ "Localization and gene effects remain coupled; no aggregate-selective intervention." ], "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": "31591561", "title": "FUS-mediated regulation of acetylcholine receptor transcription at neuromuscular junctions is compromised in amyotrophic lateral sclerosis.", "citation": "Picchiarelli G, Demestre M, Zuko A et al. FUS-mediated regulation of acetylcholine receptor transcription at neuromuscular junctions is compromised in amyotrophic lateral sclerosis. Nature neuroscience. 2019.", "doi": "10.1038/s41593-019-0498-9", "pmcid": "PMC6858880", "url": "https://pubmed.ncbi.nlm.nih.gov/31591561/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31591561/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "Erratum in: PMID 42463858" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID31591561", "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": "Strong", "system": "FUS knock-in mouse NMJs", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Muscle-intrinsic postsynaptic defects precede motor-neuron loss.", "what_it_does_not_show": "Same mutant lineage reused; erratum42463858 details unaudited.", "confounders_present": [ "Same mutant lineage reused; erratum42463858 details unaudited." ], "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": "32187538", "title": "Mice Carrying ALS Mutant TDP-43, but Not Mutant FUS, Display In Vivo Defects in Axonal Transport of Signaling Endosomes.", "citation": "Sleigh JN, Tosolini AP, Gordon D et al. Mice Carrying ALS Mutant TDP-43, but Not Mutant FUS, Display In Vivo Defects in Axonal Transport of Signaling Endosomes. Cell reports. 2020.", "doi": "10.1016/j.celrep.2020.02.078", "pmcid": "PMC7090381", "url": "https://pubmed.ncbi.nlm.nih.gov/32187538/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32187538/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID32187538", "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": "TDP and FUS mouse transport", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "TDP transport defects are absent in FUSDelta14 despite neuron loss.", "what_it_does_not_show": "Shared FUS line; separates one pathway rather than excluding all cytoplasmic toxicity.", "confounders_present": [ "Shared FUS line; separates one pathway rather than excluding all cytoplasmic toxicity." ], "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": [ "Shared FUSDelta14 line." ] }, { "n": 38, "pmid": "26951610", "title": "Toxic gain of function from mutant FUS protein is crucial to trigger cell autonomous motor neuron loss.", "citation": "Scekic-Zahirovic J, Sendscheid O, El Oussini H et al. Toxic gain of function from mutant FUS protein is crucial to trigger cell autonomous motor neuron loss. The EMBO journal. 2016.", "doi": "10.15252/embj.201592559", "pmcid": "PMC4868956", "url": "https://pubmed.ncbi.nlm.nih.gov/26951610/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26951610/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID26951610", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph18, 1:Results:paragraph73, 1:Results:paragraph78, 1:Results:paragraph79, 1:Results:paragraph83. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "FUSDeltaNLS versus FUS-null mice", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Mutant but not null causes neonatal motor loss; allele reversion rescues cell bodies.", "what_it_does_not_show": "Perinatal homozygous model; death not rescued; WT restoration removes mutant and restores nuclear function together.", "confounders_present": [ "Perinatal homozygous model; death not rescued; WT restoration removes mutant and restores nuclear function together." ], "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": "26842965", "title": "ALS-associated mutant FUS induces selective motor neuron degeneration through toxic gain of function.", "citation": "Sharma A, Lyashchenko AK, Lu L et al. ALS-associated mutant FUS induces selective motor neuron degeneration through toxic gain of function. Nature communications. 2016.", "doi": "10.1038/ncomms10465", "pmcid": "PMC4742863", "url": "https://pubmed.ncbi.nlm.nih.gov/26842965/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26842965/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID26842965", "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": "mutant FUS transgenic and conditional-null mice", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Mutant gain induces degeneration while postnatal FUS loss alone does not.", "what_it_does_not_show": "Transgenic dose and developmental timing constrain generalization.", "confounders_present": [ "Transgenic dose and developmental timing 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": 40, "pmid": "29053787", "title": "Humanized mutant FUS drives progressive motor neuron degeneration without aggregation in 'FUSDelta14' knockin mice.", "citation": "Devoy A, Kalmar B, Stewart M et al. Humanized mutant FUS drives progressive motor neuron degeneration without aggregation in 'FUSDelta14' knockin mice. Brain : a journal of neurology. 2017.", "doi": "10.1093/brain/awx248", "pmcid": "PMC5841203", "url": "https://pubmed.ncbi.nlm.nih.gov/29053787/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29053787/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID29053787", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 2:Results:paragraph0, 2:Results:paragraph3, 2:Results:paragraph6, 2:Results:paragraph8, 2:Results:paragraph12, 2:Results:paragraph13. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "endogenous FUSDelta14 mice", "decisive_perturbation": false, "endogenous": true, "direction": "contradicts", "what_it_shows": "Equivalent total FUS dosage yields progressive motor loss without insoluble FUS or histological inclusions.", "what_it_does_not_show": "Specific mutation and mouse lifespan; absence at tested stages does not exclude small assemblies.", "confounders_present": [ "Specific mutation and mouse lifespan; absence at tested stages does not exclude small assemblies." ], "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": [ "FUSDelta14 line reused in transport and RNA follow-ups." ] }, { "n": 41, "pmid": "32479602", "title": "FUS ALS-causative mutations impair FUS autoregulation and splicing factor networks through intron retention.", "citation": "Humphrey J, Birsa N, Milioto C et al. FUS ALS-causative mutations impair FUS autoregulation and splicing factor networks through intron retention. Nucleic acids research. 2020.", "doi": "10.1093/nar/gkaa410", "pmcid": "PMC7337901", "url": "https://pubmed.ncbi.nlm.nih.gov/32479602/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32479602/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID32479602", "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", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "FUS knock-in and knockout RNA", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "FUS autoregulatory splicing and expression networks differ across mutant and loss states.", "what_it_does_not_show": "Same knock-in family; transcriptome perturbation not sufficient causal course proof.", "confounders_present": [ "Same knock-in family; transcriptome perturbation not sufficient causal course 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": [ "Shared FUSDelta14 line." ] }, { "n": 42, "pmid": "28243725", "title": "Motor neuron intrinsic and extrinsic mechanisms contribute to the pathogenesis of FUS-associated amyotrophic lateral sclerosis.", "citation": "Scekic-Zahirovic J, Oussini HE, Mersmann S et al. Motor neuron intrinsic and extrinsic mechanisms contribute to the pathogenesis of FUS-associated amyotrophic lateral sclerosis. Acta neuropathologica. 2017.", "doi": "10.1007/s00401-017-1687-9", "pmcid": "PMC5427169", "url": "https://pubmed.ncbi.nlm.nih.gov/28243725/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28243725/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID28243725", "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": "Strong", "system": "conditional single-copy FUS mice", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Motor-neuron WT allele reversion saves cell bodies but only delays symptoms.", "what_it_does_not_show": "Residual axonal and neighboring-cell pathology limits whole-course rescue.", "confounders_present": [ "Residual axonal and neighboring-cell pathology limits whole-course 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": 43, "pmid": "23382207", "title": "ALS-linked TDP-43 mutations produce aberrant RNA splicing and adult-onset motor neuron disease without aggregation or loss of nuclear TDP-43.", "citation": "Arnold ES, Ling SC, Huelga SC et al. ALS-linked TDP-43 mutations produce aberrant RNA splicing and adult-onset motor neuron disease without aggregation or loss of nuclear TDP-43. Proceedings of the National Academy of Sciences of the United States of America. 2013.", "doi": "10.1073/pnas.1222809110", "pmcid": "PMC3581922", "url": "https://pubmed.ncbi.nlm.nih.gov/23382207/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/23382207/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID23382207", "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", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "near-endogenous-pattern mutant TDP mice", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Adult motor disease and RNA gain/loss occur without insoluble aggregates or nuclear depletion.", "what_it_does_not_show": "Transgene is not an endogenous knock-in; small assemblies not excluded.", "confounders_present": [ "Transgene is not an endogenous knock-in; small assemblies not excluded." ], "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": "28357566", "title": "Mutant TDP-43 within motor neurons drives disease onset but not progression in amyotrophic lateral sclerosis.", "citation": "Ditsworth D, Maldonado M, McAlonis-Downes M et al. Mutant TDP-43 within motor neurons drives disease onset but not progression in amyotrophic lateral sclerosis. Acta neuropathologica. 2017.", "doi": "10.1007/s00401-017-1698-6", "pmcid": "PMC5427168", "url": "https://pubmed.ncbi.nlm.nih.gov/28357566/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28357566/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID28357566", "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": "Strong", "system": "conditional mutant TDP mice", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Motor-neuron mutant excision prevents cell-body loss but not all axon/glial progression.", "what_it_does_not_show": "Cell restriction and incomplete rescue argue against neuron-only single mechanism.", "confounders_present": [ "Cell restriction and incomplete rescue argue against neuron-only single 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": 45, "pmid": "29556029", "title": "TDP-43 gains function due to perturbed autoregulation in a Tardbp knock-in mouse model of ALS-FTD.", "citation": "White MA, Kim E, Duffy A et al. TDP-43 gains function due to perturbed autoregulation in a Tardbp knock-in mouse model of ALS-FTD. Nature neuroscience. 2018.", "doi": "10.1038/s41593-018-0113-5", "pmcid": "PMC5884423", "url": "https://pubmed.ncbi.nlm.nih.gov/29556029/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29556029/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "Erratum in: PMID 29872124" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID29556029", "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", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "TardbpQ331K endogenous knock-in mice", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Autoregulation and RNA function are perturbed with cognitive/interneuron phenotypes.", "what_it_does_not_show": "KI does not ensure unchanged total dose; erratum29872124 details unaudited.", "confounders_present": [ "KI does not ensure unchanged total dose; erratum29872124 details unaudited." ], "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": "21206091", "title": "Dysregulation of the ALS-associated gene TDP-43 leads to neuronal death and degeneration in mice.", "citation": "Igaz LM, Kwong LK, Lee EB et al. Dysregulation of the ALS-associated gene TDP-43 leads to neuronal death and degeneration in mice. The Journal of clinical investigation. 2011.", "doi": "10.1172/JCI44867", "pmcid": "PMC3026736", "url": "https://pubmed.ncbi.nlm.nih.gov/21206091/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/21206091/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID21206091", "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", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "WT and deltaNLS TDP transgenic mice", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Degeneration occurs with few inclusions and downregulation of endogenous TDP.", "what_it_does_not_show": "Overexpression and autoregulation confound compartment-specific attribution.", "confounders_present": [ "Overexpression and autoregulation confound compartment-specific attribution." ], "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": "29650702", "title": "RNA buffers the phase separation behavior of prion-like RNA binding proteins.", "citation": "Maharana S, Wang J, Papadopoulos DK et al. RNA buffers the phase separation behavior of prion-like RNA binding proteins. Science (New York, N.Y.). 2018.", "doi": "10.1126/science.aar7366", "pmcid": "PMC6091854", "url": "https://pubmed.ncbi.nlm.nih.gov/29650702/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29650702/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID29650702", "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", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "RNA buffering in cells and biophysics", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "RNA concentration and binding tune RBP demixing and cell toxicity.", "what_it_does_not_show": "RNA buffering is not proof of initiating disease failure in vivo.", "confounders_present": [ "RNA buffering is not proof of initiating disease failure in vivo." ], "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": "35112738", "title": "Disease-linked TDP-43 hyperphosphorylation suppresses TDP-43 condensation and aggregation.", "citation": "Gruijs da Silva LA, Simonetti F, Hutten S et al. Disease-linked TDP-43 hyperphosphorylation suppresses TDP-43 condensation and aggregation. The EMBO journal. 2022.", "doi": "10.15252/embj.2021108443", "pmcid": "PMC9016352", "url": "https://pubmed.ncbi.nlm.nih.gov/35112738/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35112738/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID35112738", "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" ], "favors_models": [], "evidence_class": "Moderate", "system": "phosphomimetic TDP cells and proteins", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Phosphomimetic changes suppress aggregation while retaining import and RNA function.", "what_it_does_not_show": "Protective disease-course effects are proposed rather than established.", "confounders_present": [ "Protective disease-course effects are proposed rather than established." ], "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": "40414239", "title": "Antisense oligonucleotide jacifusen for FUS-ALS: an investigator-initiated, multicentre, open-label case series.", "citation": "Shneider NA, Harms MB, Korobeynikov VA et al. Antisense oligonucleotide jacifusen for FUS-ALS: an investigator-initiated, multicentre, open-label case series. Lancet (London, England). 2025.", "doi": "10.1016/S0140-6736(25)00513-6", "pmcid": "PMC12407188", "url": "https://pubmed.ncbi.nlm.nih.gov/40414239/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40414239/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "Erratum in: PMID 40849137" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID40414239", "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:paragraph4, 2:Results:paragraph5, 2:Results:paragraph6, 2:Results:paragraph7, 2:Results:paragraph8. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "12-person expanded-access jacifusen series", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Target engagement and neurofilament reductions coexist with one functional recovery and frequent continued decline.", "what_it_does_not_show": "Open-label heterogeneous variants and dosing; prior single patient reused; erratum40849137 unaudited.", "confounders_present": [ "Open-label heterogeneous variants and dosing; prior single patient reused; erratum40849137 unaudited." ], "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": [ "Participant1 previously reported in PMID35075293; not independent human efficacy." ] }, { "n": 50, "pmid": "36075972", "title": "Heat-shock chaperone HSPB1 regulates cytoplasmic TDP-43 phase separation and liquid-to-gel transition.", "citation": "Lu S, Hu J, Arogundade OA et al. Heat-shock chaperone HSPB1 regulates cytoplasmic TDP-43 phase separation and liquid-to-gel transition. Nature cell biology. 2022.", "doi": "10.1038/s41556-022-00988-8", "pmcid": "PMC9872726", "url": "https://pubmed.ncbi.nlm.nih.gov/36075972/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36075972/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID36075972", "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", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "stress cells and human postmortem", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "HSPB1 restrains cytoplasmic gel/fibril states and is reduced in some affected neurons.", "what_it_does_not_show": "Forced stress and postmortem chaperone loss cannot identify endogenous necessity.", "confounders_present": [ "Forced stress and postmortem chaperone loss cannot identify endogenous 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": 51, "pmid": "37431963", "title": "Loss of TDP-43 oligomerization or RNA binding elicits distinct aggregation patterns.", "citation": "Pérez-Berlanga M, Wiersma VI, Zbinden A et al. Loss of TDP-43 oligomerization or RNA binding elicits distinct aggregation patterns. The EMBO journal. 2023.", "doi": "10.15252/embj.2022111719", "pmcid": "PMC10476175", "url": "https://pubmed.ncbi.nlm.nih.gov/37431963/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37431963/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID37431963", "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", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "near-physiological human neurons", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Structured oligomer and RNA-binding changes alter stability splicing and aggregation.", "what_it_does_not_show": "Properties change together; journal 2023 replaces the repository/preprint date.", "confounders_present": [ "Properties change together; journal 2023 replaces the repository/preprint date." ], "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": "33335017", "title": "HSP70 chaperones RNA-free TDP-43 into anisotropic intranuclear liquid spherical shells.", "citation": "Yu H, Lu S, Gasior K et al. HSP70 chaperones RNA-free TDP-43 into anisotropic intranuclear liquid spherical shells. Science (New York, N.Y.). 2021.", "doi": "10.1126/science.abb4309", "pmcid": "PMC8286096", "url": "https://pubmed.ncbi.nlm.nih.gov/33335017/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33335017/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID33335017", "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", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "nuclear anisosome cells and in vivo challenge", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "HSP70/ATP regulate liquid shells and solidification of TDP assemblies.", "what_it_does_not_show": "Proteasome challenge and nuclear material state are not sporadic ALS initiation.", "confounders_present": [ "Proteasome challenge and nuclear material state are not sporadic ALS initiation." ], "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": "23104007", "title": "Inhibition of RNA lariat debranching enzyme suppresses TDP-43 toxicity in ALS disease models.", "citation": "Armakola M, Higgins MJ, Figley MD et al. Inhibition of RNA lariat debranching enzyme suppresses TDP-43 toxicity in ALS disease models. Nature genetics. 2012.", "doi": "10.1038/ng.2434", "pmcid": "PMC3510335", "url": "https://pubmed.ncbi.nlm.nih.gov/23104007/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/23104007/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID23104007", "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": "yeast and rat neuron TDP models", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "DBR1-dependent RNA lariats buffer TDP toxicity.", "what_it_does_not_show": "Forced expression and RNA pleiotropy; no disease survival.", "confounders_present": [ "Forced expression and RNA pleiotropy; no disease survival." ], "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": "20071528", "title": "Cytoplasmic mislocalization of TDP-43 is toxic to neurons and enhanced by a mutation associated with familial amyotrophic lateral sclerosis.", "citation": "Barmada SJ, Skibinski G, Korb E et al. Cytoplasmic mislocalization of TDP-43 is toxic to neurons and enhanced by a mutation associated with familial amyotrophic lateral sclerosis. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2010.", "doi": "10.1523/JNEUROSCI.4988-09.2010", "pmcid": "PMC2821110", "url": "https://pubmed.ncbi.nlm.nih.gov/20071528/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/20071528/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID20071528", "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", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "longitudinal single rat neurons", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Diffuse cytoplasmic TDP predicts death; inclusion presence does not increase measured death risk.", "what_it_does_not_show": "Tagged overexpression; lack of risk association does not prove inclusions protective.", "confounders_present": [ "Tagged overexpression; lack of risk association does not prove inclusions protective." ], "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": "37000196", "title": "C-terminal frameshift variant of TDP-43 with pronounced aggregation-propensity causes rimmed vacuole myopathy but not ALS/FTD.", "citation": "Ervilha Pereira P, Schuermans N, Meylemans A et al. C-terminal frameshift variant of TDP-43 with pronounced aggregation-propensity causes rimmed vacuole myopathy but not ALS/FTD. Acta neuropathologica. 2023.", "doi": "10.1007/s00401-023-02565-1", "pmcid": "PMC10175433", "url": "https://pubmed.ncbi.nlm.nih.gov/37000196/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37000196/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID37000196", "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", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "TARDBP myopathy family and neurons", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Aggregation-prone frameshift is less neuron-toxic with partial functional loss.", "what_it_does_not_show": "Myopathy is a different phenotype; not broad protective aggregate evidence.", "confounders_present": [ "Myopathy is a different phenotype; not broad protective aggregate evidence." ], "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": "22718760", "title": "Targeted depletion of TDP-43 expression in the spinal cord motor neurons leads to the development of amyotrophic lateral sclerosis-like phenotypes in mice.", "citation": "Wu LS, Cheng WC, Shen CK et al. Targeted depletion of TDP-43 expression in the spinal cord motor neurons leads to the development of amyotrophic lateral sclerosis-like phenotypes in mice. The Journal of biological chemistry. 2012.", "doi": "10.1074/jbc.M112.359000", "pmcid": "PMC3431639", "url": "https://pubmed.ncbi.nlm.nih.gov/22718760/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/22718760/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID22718760", "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": "motor-specific Tardbp-null mice", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Conditional loss yields progressive motor-neuron loss and glial activation.", "what_it_does_not_show": "Loss of essential protein is not selective cryptic-splicing disruption alone.", "confounders_present": [ "Loss of essential protein is not selective cryptic-splicing disruption 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": 57, "pmid": "41720774", "title": "A neurotoxic cryptic peptide arising from TDP-43-dependent cryptic splicing of PKN1.", "citation": "Yang M, Wang Q, Yan R et al. A neurotoxic cryptic peptide arising from TDP-43-dependent cryptic splicing of PKN1. Nature communications. 2026.", "doi": "10.1038/s41467-026-68916-0", "pmcid": "PMC13035944", "url": "https://pubmed.ncbi.nlm.nih.gov/41720774/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/41720774/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID41720774", "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": "cryptic peptide expression and mice", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "A cryptic PKN peptide escaping NMD can impair cognition in an expression model.", "what_it_does_not_show": "Ectopic peptide toxicity is not endogenous ALS necessity.", "confounders_present": [ "Ectopic peptide toxicity is not 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": 58, "pmid": "37819053", "title": "RNA-binding deficient TDP-43 drives cognitive decline in a mouse model of TDP-43 proteinopathy.", "citation": "Necarsulmer JC, Simon JM, Evangelista BA et al. RNA-binding deficient TDP-43 drives cognitive decline in a mouse model of TDP-43 proteinopathy. eLife. 2023.", "doi": "10.7554/eLife.85921", "pmcid": "PMC10567115", "url": "https://pubmed.ncbi.nlm.nih.gov/37819053/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37819053/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "Update of: PMID not supplied", "Update of: PMID not supplied", "Update of: PMID not supplied" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID37819053", "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", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "endogenous TDP K145Q mice", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "RNA-binding impairment precedes cognitive and pathological progression.", "what_it_does_not_show": "Acetyl-mimic mutation is not identical to a natural acetylation state.", "confounders_present": [ "Acetyl-mimic mutation is not identical to a natural acetylation state." ], "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": "29311743", "title": "TDP-43 pathology disrupts nuclear pore complexes and nucleocytoplasmic transport in ALS/FTD.", "citation": "Chou CC, Zhang Y, Umoh ME et al. TDP-43 pathology disrupts nuclear pore complexes and nucleocytoplasmic transport in ALS/FTD. Nature neuroscience. 2018.", "doi": "10.1038/s41593-017-0047-3", "pmcid": "PMC5800968", "url": "https://pubmed.ncbi.nlm.nih.gov/29311743/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29311743/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID29311743", "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": "cells iPSC and human pathology", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "TDP pathological assemblies associate with nuclear-pore disruption.", "what_it_does_not_show": "Cell assays and tissue association lack organismal trajectory rescue; journal 2018 replaces conference 2017.", "confounders_present": [ "Cell assays and tissue association lack organismal trajectory rescue; journal 2018 replaces conference 2017." ], "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": "40753166", "title": "Sporadic ALS induced pluripotent stem cell derived neurons reveal hallmarks of TDP-43 loss of function.", "citation": "Rothstein JD, Keeley O, Warlick C et al. Sporadic ALS induced pluripotent stem cell derived neurons reveal hallmarks of TDP-43 loss of function. Nature communications. 2025.", "doi": "10.1038/s41467-025-62482-7", "pmcid": "PMC12318032", "url": "https://pubmed.ncbi.nlm.nih.gov/40753166/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40753166/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID40753166", "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": "180 human iPSC donors and tissue", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Variable TDP loss signatures track nuclear pores; POM121 repair restores RNA function.", "what_it_does_not_show": "Cellular repair and donor association not clinical course rescue.", "confounders_present": [ "Cellular repair and donor association not clinical course 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": 61, "pmid": "31519910", "title": "The mutational landscape of a prion-like domain.", "citation": "Bolognesi B, Faure AJ, Seuma M et al. The mutational landscape of a prion-like domain. Nature communications. 2019.", "doi": "10.1038/s41467-019-12101-z", "pmcid": "PMC6744496", "url": "https://pubmed.ncbi.nlm.nih.gov/31519910/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31519910/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID31519910", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph4, 1:Results:paragraph6, 1:Results:paragraph7, 1:Results:paragraph9, 1:Results:paragraph10. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "yeast deep mutational scanning", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Hydrophobic solid-like aggregates correlate with less toxicity than dynamic peripheral foci.", "what_it_does_not_show": "Yeast forced expression and multifactorial sequence changes; not proof all human aggregates protect.", "confounders_present": [ "Yeast forced expression and multifactorial sequence changes; not proof all human aggregates protect." ], "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": "25088712", "title": "Aggregate formation prevents dTDP-43 neurotoxicity in the Drosophila melanogaster eye.", "citation": "Cragnaz L, Klima R, Skoko N et al. Aggregate formation prevents dTDP-43 neurotoxicity in the Drosophila melanogaster eye. Neurobiology of disease. 2014.", "doi": "10.1016/j.nbd.2014.07.009", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/25088712/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25088712/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID25088712", "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" ], "favors_models": [], "evidence_class": "Moderate", "system": "Drosophila eye overexpression", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Artificial aggregates sequester TBPH and protect the eye from overexpression toxicity.", "what_it_does_not_show": "Developmental eye context and TDP dispensability limit disease relevance.", "confounders_present": [ "Developmental eye context and TDP dispensability limit disease relevance." ], "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": "31332509", "title": "Splicing repression is a major function of TDP-43 in motor neurons.", "citation": "Donde A, Sun M, Ling JP et al. Splicing repression is a major function of TDP-43 in motor neurons. Acta neuropathologica. 2019.", "doi": "10.1007/s00401-019-02042-8", "pmcid": "PMC6802294", "url": "https://pubmed.ncbi.nlm.nih.gov/31332509/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31332509/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID31332509", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Materials and Methods:paragraph9, 1:Materials and Methods:paragraph10, 1:Materials and Methods:paragraph11, 1:Materials and Methods:paragraph12, 1:Materials and Methods:paragraph13, 2:Results:paragraph0, 2:Results:paragraph2, 2:Results:paragraph3, 2:Results:paragraph4, 2:Results:paragraph5, 2:Results:paragraph6. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "Tardbp-null flies and motor-neuron-null mice", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "A chimeric splicing repressor rescues motor function and extends mouse median survival by 29 weeks in two cohorts.", "what_it_does_not_show": "Neonatal AAV and knockout not sporadic initiation; litter-level randomization and delivery attrition; same Ling programme.", "confounders_present": [ "Neonatal AAV and knockout not sporadic initiation; litter-level randomization and delivery attrition; same Ling programme." ], "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": [ "Ling/Donde chimeric-repressor programme shared; two mouse cohorts are within-study replication." ] } ], "verification_summary": { "load_bearing_claims_checked": 69, "verified": 69, "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": "association without temporal or perturbational proof caps at Β.", "specific_trigger": "Original neuropathology establishes distinct pathology classes, but prevalence alone is association and cannot assign causal function. Selected case series do not license population percentages.", "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": "Biophysical and forced-assembly toxicity are plausible, but no selective macroscopic-aggregate intervention retaining soluble abundance and nuclear function establishes disease-relevant necessity. Aggregate-free degeneration and restricted protective sequestration are real discriminators.", "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": "Postmortem proteinopathy, genotype models and rescues support plausible interacting pathways. No selective model-independent correction establishes this principal aggregate-driven dual mechanism across prespecified sporadic ALS–FTD contexts.", "resulting_ceiling": "Γ" } ], "cap_precedence_resolutions": [ { "collision": "Perturbation in a defined setting versus broader inference", "subclaim_scope_cap_binds_on": "Mislocalization and aggregation of TDP-43 and FUS is the principal causal driver of neurodegeneration across ALS-FTD through nuclear loss of function and cytoplasmic toxic gain of function.", "subclaim_scope_threshold_binds_on": "The precise experimentally tested subclaim scope", "resolution": "Convergence licenses Ζ for the precisely tested nuclear RNA-function contribution, including in vivo trajectory rescue; cell-only caps do not erase the assembled case. Those sources cannot upgrade the broader aggregate-specific or sporadic-principal claims. Endogenous mutant FUS supports Ε at its genetic scope; total FUS lowering is not selective aggregate removal.", "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": "", "gamma_hard_rules_triggered": [ "Overexpression, optogenetics and seeding demonstrate capacity rather than endogenous disease necessity.", "Physiological abundance is checked empirically; an endogenous knock-in can perturb autoregulation.", "Transcript or inclusion rescue is separated from motor function, neuron survival and organismal trajectory.", "Familial FUS or TARDBP etiology does not establish all-sporadic aggregate causation.", "Macroscopic inclusions, soluble assemblies, liquid condensates and insolubility have distinct measurements." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "Original neuropathology establishes distinct pathology classes, but prevalence alone is association and cannot assign causal function. Selected case series do not license population percentages.", "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": "PMID26250685, PMID35197628, PMID36927019, PMID35197626, PMID30643292, PMID30643298, PMID35767949, PMID37996528, PMID42234776, PMID22718760, PMID31332509", "gamma_hard_rules_triggered": [ "Overexpression, optogenetics and seeding demonstrate capacity rather than endogenous disease necessity.", "Physiological abundance is checked empirically; an endogenous knock-in can perturb autoregulation.", "Transcript or inclusion rescue is separated from motor function, neuron survival and organismal trajectory.", "Familial FUS or TARDBP etiology does not establish all-sporadic aggregate causation.", "Macroscopic inclusions, soluble assemblies, liquid condensates and insolubility have distinct measurements." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "yes", "perturbation_result_note": "Endogenous TDP depletion, UG/splice-site engineering, RNA-binding competent rescue, human axon/synaptic correction and chimeric-repressor rescue of motor function and survival in flies/mice converge on a functional contribution. Targets are species-specific and knockout rescue does not establish sporadic initiation.", "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": "PMID35075293, PMID26951610, PMID28243725", "gamma_hard_rules_triggered": [ "Overexpression, optogenetics and seeding demonstrate capacity rather than endogenous disease necessity.", "Physiological abundance is checked empirically; an endogenous knock-in can perturb autoregulation.", "Transcript or inclusion rescue is separated from motor function, neuron survival and organismal trajectory.", "Familial FUS or TARDBP etiology does not establish all-sporadic aggregate causation.", "Macroscopic inclusions, soluble assemblies, liquid condensates and insolubility have distinct measurements." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "yes", "perturbation_result_note": "Independent endogenous mutant-FUS lines, null comparisons, cell-restricted allele reversal and FUS lowering identify toxic gain in familial-mutant mouse contexts. Nuclear restoration and mutant removal are coupled; stage and total-dose controls matter.", "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": "", "gamma_hard_rules_triggered": [ "Overexpression, optogenetics and seeding demonstrate capacity rather than endogenous disease necessity.", "Physiological abundance is checked empirically; an endogenous knock-in can perturb autoregulation.", "Transcript or inclusion rescue is separated from motor function, neuron survival and organismal trajectory.", "Familial FUS or TARDBP etiology does not establish all-sporadic aggregate causation.", "Macroscopic inclusions, soluble assemblies, liquid condensates and insolubility have distinct measurements." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "Biophysical and forced-assembly toxicity are plausible, but no selective macroscopic-aggregate intervention retaining soluble abundance and nuclear function establishes disease-relevant necessity. Aggregate-free degeneration and restricted protective sequestration are real discriminators.", "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": "", "gamma_hard_rules_triggered": [ "Overexpression, optogenetics and seeding demonstrate capacity rather than endogenous disease necessity.", "Physiological abundance is checked empirically; an endogenous knock-in can perturb autoregulation.", "Transcript or inclusion rescue is separated from motor function, neuron survival and organismal trajectory.", "Familial FUS or TARDBP etiology does not establish all-sporadic aggregate causation.", "Macroscopic inclusions, soluble assemblies, liquid condensates and insolubility have distinct measurements." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "Postmortem proteinopathy, genotype models and rescues support plausible interacting pathways. No selective model-independent correction establishes this principal aggregate-driven dual mechanism across prespecified sporadic ALS–FTD contexts.", "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": [], "what_would_cross_it": "A prevalence observation remains descriptive; separately trace cell-specific pathology before dysfunction and test its causal correction." }, { "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] UG-dependent cryptic splicing and chimeric repressor cell-survival rescue.", "[2] UNC13A risk variants potentiate TDP-dependent cryptic splicing and protein loss.", "[4] Endogenous splice-site edits and ASOs restore STMN2 and human axon regeneration.", "[7] TDP depletion reduces UNC13A; risk haplotypes amplify cryptic exon use and RNA-binding competent rescue.", "[8] STMN2 loss follows TDP depletion; stabilization restores axonal regeneration.", "[9] STMN2 correction restores axon regeneration after nuclear TDP dysfunction.", "[12] STMN2 is needed for motor-unit maintenance; knockout denervates fast-fatigable NMJs.", "[30] STMN2 loss alters axon caliber conduction denervation and motor behavior.", "[31] Combined correction of KALRN RAP1GAP SYT7 KCNQ2 nearly restores synaptic function after TDP loss.", "[56] Conditional loss yields progressive motor-neuron loss and glial activation.", "[63] A chimeric splicing repressor rescues motor function and extends mouse median survival by 29 weeks in two cohorts." ], "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] UG-dependent cryptic splicing and chimeric repressor cell-survival rescue.", "[2] UNC13A risk variants potentiate TDP-dependent cryptic splicing and protein loss.", "[4] Endogenous splice-site edits and ASOs restore STMN2 and human axon regeneration.", "[7] TDP depletion reduces UNC13A; risk haplotypes amplify cryptic exon use and RNA-binding competent rescue.", "[8] STMN2 loss follows TDP depletion; stabilization restores axonal regeneration.", "[9] STMN2 correction restores axon regeneration after nuclear TDP dysfunction.", "[12] STMN2 is needed for motor-unit maintenance; knockout denervates fast-fatigable NMJs.", "[30] STMN2 loss alters axon caliber conduction denervation and motor behavior.", "[31] Combined correction of KALRN RAP1GAP SYT7 KCNQ2 nearly restores synaptic function after TDP loss.", "[56] Conditional loss yields progressive motor-neuron loss and glial activation.", "[63] A chimeric splicing repressor rescues motor function and extends mouse median survival by 29 weeks in two cohorts." ], "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] UG-dependent cryptic splicing and chimeric repressor cell-survival rescue.", "[2] UNC13A risk variants potentiate TDP-dependent cryptic splicing and protein loss.", "[4] Endogenous splice-site edits and ASOs restore STMN2 and human axon regeneration.", "[7] TDP depletion reduces UNC13A; risk haplotypes amplify cryptic exon use and RNA-binding competent rescue.", "[8] STMN2 loss follows TDP depletion; stabilization restores axonal regeneration.", "[9] STMN2 correction restores axon regeneration after nuclear TDP dysfunction.", "[12] STMN2 is needed for motor-unit maintenance; knockout denervates fast-fatigable NMJs.", "[30] STMN2 loss alters axon caliber conduction denervation and motor behavior.", "[31] Combined correction of KALRN RAP1GAP SYT7 KCNQ2 nearly restores synaptic function after TDP loss.", "[56] Conditional loss yields progressive motor-neuron loss and glial activation.", "[63] A chimeric splicing repressor rescues motor function and extends mouse median survival by 29 weeks in two cohorts." ], "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] UG-dependent cryptic splicing and chimeric repressor cell-survival rescue.", "[2] UNC13A risk variants potentiate TDP-dependent cryptic splicing and protein loss.", "[4] Endogenous splice-site edits and ASOs restore STMN2 and human axon regeneration.", "[7] TDP depletion reduces UNC13A; risk haplotypes amplify cryptic exon use and RNA-binding competent rescue.", "[8] STMN2 loss follows TDP depletion; stabilization restores axonal regeneration.", "[9] STMN2 correction restores axon regeneration after nuclear TDP dysfunction.", "[12] STMN2 is needed for motor-unit maintenance; knockout denervates fast-fatigable NMJs.", "[30] STMN2 loss alters axon caliber conduction denervation and motor behavior.", "[31] Combined correction of KALRN RAP1GAP SYT7 KCNQ2 nearly restores synaptic function after TDP loss.", "[56] Conditional loss yields progressive motor-neuron loss and glial activation.", "[63] A chimeric splicing repressor rescues motor function and extends mouse median survival by 29 weeks in two cohorts." ], "what_would_cross_it": "Replicate physiological selective splicing-function restoration after onset in independent sporadic contexts with motor/cognitive trajectory endpoints." }, { "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": [ "[24] Dose and conditional FUS contrasts identify mutant toxicity; P1 ION363 prevents motor-neuron loss and denervation while active.", "[38] Mutant but not null causes neonatal motor loss; allele reversion rescues cell bodies.", "[42] Motor-neuron WT allele reversion saves cell bodies but only delays symptoms." ], "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": [ "[24] Dose and conditional FUS contrasts identify mutant toxicity; P1 ION363 prevents motor-neuron loss and denervation while active.", "[38] Mutant but not null causes neonatal motor loss; allele reversion rescues cell bodies.", "[42] Motor-neuron WT allele reversion saves cell bodies but only delays symptoms." ], "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": [ "[24] Dose and conditional FUS contrasts identify mutant toxicity; P1 ION363 prevents motor-neuron loss and denervation while active.", "[38] Mutant but not null causes neonatal motor loss; allele reversion rescues cell bodies.", "[42] Motor-neuron WT allele reversion saves cell bodies but only delays symptoms." ], "what_would_cross_it": "Separate localization from restored nuclear function and total soluble dosage in independent physiological humanized contexts with post-onset rescue." }, { "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": [], "what_would_cross_it": "Block and restore only macroscopic assembly while retaining nuclear RNA processing and soluble protein, then show concordant neuron and disease-course change." }, { "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": [], "what_would_cross_it": "Prospectively stratify sporadic ALS and FTD; selectively correct both arms independently and jointly at endogenous dose, measure temporal mediation and sustained disease-course rescue." } ], "generalization_check": { "generalization_tested": "yes", "context_boundary_mapped": "yes", "internal_negative_controls": [ "NTDP versus CTR and GFP, breeder-matched cohorts and blinded behavior in knockout rescue (PMID31332509).", "STMN2 splice-acceptor versus polyadenylation edits and MCP-only steric rescue (PMID36927019).", "FUS-null versus deltaNLS, ChAT-Cre reversion and neighboring-cell controls (PMID26951610).", "Equal total FUS protein and age-matched WT in Delta14 mice (PMID29053787).", "NTC ASO, time-dependent drug loss and allele-dose contrasts (PMID35075293).", "Higher non-toxic mutant protein abundance and FRAP state measurements in yeast (PMID31519910)." ], "note": "Genotype, species, developmental timing and tissue define boundaries before results. STMN2/UNC13A human sequences differ from rodents. FUS-positive TDP-negative FTD, aggregate-free mutant models and non-cell-autonomous residual pathology constrain a single mechanism. The corpus is not a prevalence survey and no exact pan-ALS proteinopathy percentages are inferred." }, "falsification_patterns_met": [ { "pattern": "Disease occurs without the claimed obligatory feature", "evidence": "Physiological FUSDelta14 motor loss without visible inclusions or detected insoluble FUS (PMID29053787); no inference that all small assemblies are absent.", "downgrade_applied": false } ], "pitfalls_flagged": [ { "pitfall": "Histology reified as toxic species", "where": "TDP/FUS pathology presence is graded separately from aggregation-selective causality." }, { "pitfall": "Molecular rescue inflated", "where": "Baughn mouse molecular target engagement is not survival rescue; Donde does measure survival." }, { "pitfall": "Near-endogenous equated with endogenous", "where": "Arnold transgene and White autoregulatory knock-in have distinct dose limitations." }, { "pitfall": "Shared cases counted as replication", "where": "Jacifusen participant 1 and shared FUSDelta14 line are flagged." }, { "pitfall": "Provider citation substitution", "where": "Consensus broad Baughn aggregate-free attribution corrected to Arnold/Devoy; journal versions replace preprints." } ], "causal_tally_audit": { "tally_claimed_by_document": 31, "tally_after_audit": 31, "items_rejected": [ "Null and negative contrasts are discriminators, not positive threshold crossings. Reports and replications are not independent causal lines.", "Gene-level etiology, RNA restoration, aggregate-state changes and clinical biomarkers are different causal endpoints.", "Negative aggregate-free/protective contrasts never enter positive-causality tallies." ] }, "steelman": { "case_one_rung_higher": "One rung higher Δ: physiological mutant models, genetic etiology and coupled transgene/FUS-lowering rescues suggest genuine disease contribution by RBP dysfunction.", "case_one_rung_lower": "One rung lower Β: proteinopathy is only a postmortem correlate. That ignores the mechanistic and in vivo perturbation/rescue evidence supporting interacting pathways.", "which_rejected": "Reject Β as the nominal mechanism has functional plausibility beyond correlation; reject Δ for the exact principal aggregate-driven sporadic gate because no matching selective causal perturbation identifies that claim. Keep higher narrow subclaim grades.", "blocking_cap_threshold_or_missing_experiment": "Missing experiment: In prospectively genotyped sporadic ALS/FTD humanized models, factorially restore nuclear splicing, prevent only large cytoplasmic assembly and alter soluble cytoplasmic abundance while holding total endogenous protein constant. Start after pathology onset and reverse each rescue to test mediation." }, "final_score": { "hsef_level": "Γ", "hsef_descriptor": "Mechanistically plausible, partial system support", "confidence": "Moderate", "confidence_rationale": "Multiple independent studies across 63 primary reports with real replication in some arms, but coupled interventions that change nuclear function and mutant protein together, overexpression and forced-assembly models, and shared mouse lines standing in for independent replication remain; evidence density and reproducibility set the band, not reviewer access or correctness.", "rests_on_non_peer_reviewed_work": false, "rationale": "The preregistered scope-matched gate SC5 is Γ. Nuclear splicing failure has convergent causal and functional rescue evidence (SC2 Ζ), and physiological mutant-FUS toxicity is context-valid (SC3 Ε). Neither establishes selective macroscopic-aggregate toxicity or principal dual-arm causation across sporadic ALS–FTD. No narrow success silently replaces that broad gate." }, "role_of_mechanism": { "classification": "reinforcing / stabilizing factor", "derivation_step_matched": 5, "derivation": "For supported RNA/protein dysfunction, pathological feedback can sustain or amplify degeneration downstream of diverse etiologies. Necessity plus sufficiency for all sporadic initiation is absent. Defined familial mutant alleles have etiological force, which does not license the registered broad aggregate-primary role.", "tournament_used_as_tiebreaker": false, "note": "Derived from causal direction, not tournament rank." }, "extended_scoring_MSD": { "momentum": { "value": "Mechanistic only", "artifact": "The examined 2025 jacifusen case series and 2026 multitarget cryptic-splicing study are completed reports; the jacifusen series records an ongoing efficacy trial, but that trial lowers total FUS in familial FUS-ALS and does not separate material state from nuclear loss of function across sporadic ALS-FTD, which is the registered boundary.", "justification": "The examined 2025 jacifusen case series and 2026 multitarget cryptic-splicing study are completed reports; the jacifusen series records an ongoing efficacy trial, but that trial lowers total FUS in familial FUS-ALS and does not separate material state from nuclear loss of function across sporadic ALS-FTD, which is the registered boundary." }, "stability": { "value": "Stable", "trigger": "No named pending result is claimed to move the broad aggregate-primary grade imminently.", "justification": "No named pending result is claimed to move the broad aggregate-primary grade 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": "In prospectively genotyped sporadic ALS/FTD humanized models, factorially restore nuclear splicing, prevent only large cytoplasmic assembly and alter soluble cytoplasmic abundance while holding total endogenous protein constant. Start after pathology onset and reverse each rescue to test mediation.", "readout": "Single-neuron RNA processing, soluble/insoluble state, axonal and synaptic function, motor/cognitive trajectory and survival", "critical_control": "Abundance-matched WT, aggregate-free mutants, RNA-binding controls, independent cell populations, delivery controls and blinded post-onset phenotyping", "supporting_result": "Both independently specified arms are necessary and joint correction consistently restores disease course across predefined sporadic contexts", "falsifying_result": "Degeneration persists after complete aggregate-only removal with restored splicing, or follows nuclear/soluble dysfunction independently of macroscopic state" } ], "knowledge_gaps": [ { "name": "Gap 1", "statement": "Identify which cytoplasmic species predicts and mediates native neuronal death.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 2", "statement": "Separate nuclear function from mutant removal during allele reversal.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 3", "statement": "Test post-onset splicing rescue in physiological sporadic contexts.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 4", "statement": "Humanize multiple species-specific cryptic targets before systemic inference.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 5", "statement": "Follow genotype-defined presymptomatic biomarker changes to functional loss.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 6", "statement": "Resolve cell-body versus axon and glial residual progression.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 7", "statement": "Replicate protective sequestration in native neuronal disease settings.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 8", "statement": "Distinguish clinical neurofilament/pathology engagement from efficacy.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 9", "statement": "Quantify total protein and autoregulation in every knock-in comparison.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 10", "statement": "Audit linked errata, supplements and inaccessible full bodies before complete-paper publication claims.", "relevance": "Limits mechanism identification or scope." } ], "review_metadata": { "review_date": "2026-10-08", "reviewer": "Codex", "evidence_base_note": "63 primary reports; literature cutoff 2026-10-08; source examination UTC date 2026-10-09; 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. SciSpace discovery was also used; matched primary leads were resolved to original records before counting. See scispace-leads.json.", "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": "Endogenous genetics, dose contrasts, cell-restricted allele reversal and therapeutic/prophylactic course endpoints are valid upper-ladder routes. They support narrow RNA/function or mutant-FUS claims without an RCT-only rule. Aggregation-selective restoration and sporadic generalization are still missing." }, { "kind": "natural_experiment", "available": false, "why_not_sufficient": "Endogenous genetics, dose contrasts, cell-restricted allele reversal and therapeutic/prophylactic course endpoints are valid upper-ladder routes. They support narrow RNA/function or mutant-FUS claims without an RCT-only rule. Aggregation-selective restoration and sporadic generalization are still missing." }, { "kind": "dose_response_across_populations", "available": false, "why_not_sufficient": "Endogenous genetics, dose contrasts, cell-restricted allele reversal and therapeutic/prophylactic course endpoints are valid upper-ladder routes. They support narrow RNA/function or mutant-FUS claims without an RCT-only rule. Aggregation-selective restoration and sporadic generalization are still missing." }, { "kind": "withdrawal_rechallenge", "available": false, "why_not_sufficient": "Endogenous genetics, dose contrasts, cell-restricted allele reversal and therapeutic/prophylactic course endpoints are valid upper-ladder routes. They support narrow RNA/function or mutant-FUS claims without an RCT-only rule. Aggregation-selective restoration and sporadic generalization are still missing." }, { "kind": "therapeutic_perturbation_hard_endpoint", "available": false, "why_not_sufficient": "Endogenous genetics, dose contrasts, cell-restricted allele reversal and therapeutic/prophylactic course endpoints are valid upper-ladder routes. They support narrow RNA/function or mutant-FUS claims without an RCT-only rule. Aggregation-selective restoration and sporadic generalization are still missing." } ], "convergence_present": true, "cap_reapplied_to_convergent_set": false }, "provenance_header": { "sources_total": 63, "claims_total": 69, "claims_verified": 69, "claims_unverified": 0, "claims_contradicted": 0, "tier_a_sources": 63, "generated_by": "Codex; HSEF v5.3", "gate_passed": true }, "claims": [ { "id": "C1", "text": "UG-dependent cryptic splicing and chimeric repressor cell-survival rescue. Whole-body disease not tested; human mouse target sequences differ.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 1 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Main text:paragraph4, 1:Main text:paragraph5, 1:Main text:paragraph6, 1:Main text:paragraph7, 1:Main text:paragraph8, 1:Main text:paragraph9, 1:Main text:paragraph10, 1:Main text:paragraph11, 1:Main text:paragraph12, 1:Main text. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C2", "text": "UNC13A risk variants potentiate TDP-dependent cryptic splicing and protein loss. Natural risk is conditional; erratum38890465 details unaudited.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 2 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C3", "text": "Cryptic transcripts yield detectable novel peptides including CSF signals. Peptide presence does not prove toxicity or initiating causality.", "carries_number": false, "load_bearing_for": [ "SC2", "SC5" ], "source_ns": [ 3 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C4", "text": "Endogenous splice-site edits and ASOs restore STMN2 and human axon regeneration. Mouse target engagement is not disease-course rescue; regenerated injury axons are restricted endpoints.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 4 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:A GU-motif confers TDP-43 binding-dependent maturation of stathmin-2 pre-mRNA, 1:TDP-43 binding sterically blocks cryptic splicing and polyadenylation of STMN2, 2:Genomic disruption of exon 2a cryptic splice site protects against misprocessing, 6:rASOs restore axonal regeneration capacity in TDP-43 deficient motor neurons, 7:rASO-mediated restoration of Stmn2 pre-mRNA processing in the mammalian CNS. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C5", "text": "Cryptic HDGFL2 biomarker can precede neurofilament rise. Temporal biomarker not causal intervention; erratum38580817 details unaudited.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 5 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C6", "text": "Truncated STMN2 tracks FTLD-TDP rather than FTLD-tau. Postmortem association and variant-specific nuclear dysfunction.", "carries_number": true, "load_bearing_for": [ "SC1", "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": "2026-10-09", "note": "" }, { "id": "C7", "text": "TDP depletion reduces UNC13A; risk haplotypes amplify cryptic exon use and RNA-binding competent rescue. Human survival association not randomized rescue; binding assay differs from companion Brown paper.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 7 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Main:paragraph2, 0:Main:paragraph5, 0:Main:paragraph6, 0:Main:paragraph18, 0:Main:paragraph19, 0:Main:paragraph20, 0:Main:paragraph21. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C8", "text": "STMN2 loss follows TDP depletion; stabilization restores axonal regeneration. Injury regeneration in culture is not ALS survival.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 8 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C9", "text": "STMN2 correction restores axon regeneration after nuclear TDP dysfunction. Shared target and culture challenge; disease trajectory untested.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 9 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C10", "text": "Nuclear TDP abnormalities and cryptic splicing map to earlier regional stages than cytoplasmic burden. Inferred timing from tissue is not longitudinal causal tracking; matched journal replaces preprint.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2", "SC4" ], "source_ns": [ 10 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C11", "text": "RNA-depleted nuclear condensates accompany persistent STMN2 splicing loss. Forced stress and coupled state-function changes do not identify sporadic initiation.", "carries_number": true, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 11 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C12", "text": "STMN2 is needed for motor-unit maintenance; knockout denervates fast-fatigable NMJs. No motor-neuron or axon degeneration in this model; not full ALS phenocopy.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 12 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C13", "text": "Blocking mitochondrial TDP import rescues neuronal and behavioral phenotypes. Overexpression and broad mitochondrial intervention do not isolate macroscopic aggregates.", "carries_number": false, "load_bearing_for": [ "SC3", "SC5" ], "source_ns": [ 13 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C14", "text": "Forced cytoplasmic assemblies are toxic and RNA antagonism reduces inclusion/toxicity. Optogenetic assembly and coupled effects cap endogenous necessity inference.", "carries_number": false, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 14 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C15", "text": "Transgene suppression improves motor course and survival with restoration of nuclear TDP. Both arms and total protein change together; overexpression model.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 15 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C16", "text": "Ataxin2 deletion or ASO extends survival and lowers pathology. Pleiotropic change does not selectively identify aggregate toxicity.", "carries_number": true, "load_bearing_for": [ "SC3", "SC5" ], "source_ns": [ 16 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C17", "text": "KCNQ2 cryptic exon produces ER-associated protein and hyperexcitability corrected by ASO. Cell-function rescue not organismal or clinical rescue.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 17 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C18", "text": "TDP loss alters cryptic polyadenylation with both stability-increasing and decreasing effects. Not all aberrant RNAs undergo NMD or cause neuronal death.", "carries_number": false, "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": "2026-10-09", "note": "" }, { "id": "C19", "text": "CHMP7 lowering restores pore/Ran/RNA defects and protects against glutamate challenge. Upstream transport perturbation and challenge survival not spontaneous disease course.", "carries_number": true, "load_bearing_for": [ "SC2", "SC5" ], "source_ns": [ 19 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C20", "text": "Nuclear import receptors counter phase transitions and rescue functional or degenerative outcomes. Import and chaperoning change together across forced models.", "carries_number": false, "load_bearing_for": [ "SC3", "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": "2026-10-09", "note": "" }, { "id": "C21", "text": "Transportin and arginine methylation regulate FUS condensation and localization. Material-state mechanism does not establish clinical primary cause.", "carries_number": false, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 21 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C22", "text": "TIA1 variants link altered granule dynamics to selected ALS/FTD families. Familial association and engineered stress cannot generalize across sporadic disease.", "carries_number": true, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 22 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C23", "text": "Small molecules modify stress-granule composition and TDP puncta. Puncta reduction lacks organismal trajectory endpoint.", "carries_number": false, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 23 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C24", "text": "Dose and conditional FUS contrasts identify mutant toxicity; P1 ION363 prevents motor-neuron loss and denervation while active. No overt motor phenotype in initial heterozygotes; prophylactic lowering changes soluble and insoluble FUS; one patient cannot establish efficacy.", "carries_number": true, "load_bearing_for": [ "SC3" ], "source_ns": [ 24 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph3, 1:Results:paragraph36, 1:Results:paragraph49, 1:Results:paragraph52, 1:Results:paragraph53, 1:Results:paragraph59. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C25", "text": "Disease filaments have structures distinct from reconstructed in vitro fibrils. Structural identity is not toxicity or necessity.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 25 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C26", "text": "Helical changes can enhance phase separation and splicing function. Condensation is not intrinsically pathogenic; reporter endpoints.", "carries_number": false, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 26 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C27", "text": "TDP protein identified in selected disease inclusions. Postmortem presence cannot assign cause.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 27 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C28", "text": "Cell-layer analysis exposes splicing defects masked by bulk RNA. Defined genetic FTD subset and observational tissue.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 28 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C29", "text": "Distinct FUS-positive TDP/tau-negative subtypes constrain a uniform protein account. Selected case series cannot estimate all-population prevalence.", "carries_number": false, "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": "2026-10-09", "note": "" }, { "id": "C30", "text": "STMN2 loss alters axon caliber conduction denervation and motor behavior. Not selective rescue of endogenous sporadic TDP disease.", "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": "2026-10-09", "note": "" }, { "id": "C31", "text": "Combined correction of KALRN RAP1GAP SYT7 KCNQ2 nearly restores synaptic function after TDP loss. Multitarget culture rescue not systemic survival; journal report deduplicated from preprint.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 31 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C32", "text": "Modified ubiquitinated TDP defines a shared pathology class. End-stage association does not resolve toxic species.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 32 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C33", "text": "Segregating variants support gene-level etiology; engineered developmental toxicity. Gene causality does not prove aggregates or all sporadic mechanism.", "carries_number": false, "load_bearing_for": [ "SC3", "SC5" ], "source_ns": [ 33 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C34", "text": "FUS mutations segregate in defined ALS families with abnormal localization. Familial etiology is not universal sporadic mechanism.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 34 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C35", "text": "Multiple familial mutations alter FUS localization. Localization and gene effects remain coupled; no aggregate-selective intervention.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 35 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C36", "text": "Muscle-intrinsic postsynaptic defects precede motor-neuron loss. Same mutant lineage reused; erratum42463858 details unaudited.", "carries_number": false, "load_bearing_for": [ "SC3", "SC5" ], "source_ns": [ 36 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C37", "text": "TDP transport defects are absent in FUSDelta14 despite neuron loss. Shared FUS line; separates one pathway rather than excluding all cytoplasmic toxicity.", "carries_number": true, "load_bearing_for": [ "SC3", "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": "2026-10-09", "note": "" }, { "id": "C38", "text": "Mutant but not null causes neonatal motor loss; allele reversion rescues cell bodies. Perinatal homozygous model; death not rescued; WT restoration removes mutant and restores nuclear function together.", "carries_number": false, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 38 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph18, 1:Results:paragraph73, 1:Results:paragraph78, 1:Results:paragraph79, 1:Results:paragraph83. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C39", "text": "Mutant gain induces degeneration while postnatal FUS loss alone does not. Transgenic dose and developmental timing constrain generalization.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 39 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C40", "text": "Equivalent total FUS dosage yields progressive motor loss without insoluble FUS or histological inclusions. Specific mutation and mouse lifespan; absence at tested stages does not exclude small assemblies.", "carries_number": false, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 40 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 2:Results:paragraph0, 2:Results:paragraph3, 2:Results:paragraph6, 2:Results:paragraph8, 2:Results:paragraph12, 2:Results:paragraph13. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C41", "text": "FUS autoregulatory splicing and expression networks differ across mutant and loss states. Same knock-in family; transcriptome perturbation not sufficient causal course proof.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 41 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C42", "text": "Motor-neuron WT allele reversion saves cell bodies but only delays symptoms. Residual axonal and neighboring-cell pathology limits whole-course rescue.", "carries_number": false, "load_bearing_for": [ "SC3", "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": "2026-10-09", "note": "" }, { "id": "C43", "text": "Adult motor disease and RNA gain/loss occur without insoluble aggregates or nuclear depletion. Transgene is not an endogenous knock-in; small assemblies not excluded.", "carries_number": false, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 43 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C44", "text": "Motor-neuron mutant excision prevents cell-body loss but not all axon/glial progression. Cell restriction and incomplete rescue argue against neuron-only single mechanism.", "carries_number": false, "load_bearing_for": [ "SC3", "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": "2026-10-09", "note": "" }, { "id": "C45", "text": "Autoregulation and RNA function are perturbed with cognitive/interneuron phenotypes. KI does not ensure unchanged total dose; erratum29872124 details unaudited.", "carries_number": false, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 45 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C46", "text": "Degeneration occurs with few inclusions and downregulation of endogenous TDP. Overexpression and autoregulation confound compartment-specific attribution.", "carries_number": false, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 46 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C47", "text": "RNA concentration and binding tune RBP demixing and cell toxicity. RNA buffering is not proof of initiating disease failure in vivo.", "carries_number": false, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 47 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C48", "text": "Phosphomimetic changes suppress aggregation while retaining import and RNA function. Protective disease-course effects are proposed rather than established.", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 48 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C49", "text": "Target engagement and neurofilament reductions coexist with one functional recovery and frequent continued decline. Open-label heterogeneous variants and dosing; prior single patient reused; erratum40849137 unaudited.", "carries_number": false, "load_bearing_for": [ "SC3", "SC5" ], "source_ns": [ 49 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 2:Results:paragraph1, 2:Results:paragraph2, 2:Results:paragraph4, 2:Results:paragraph5, 2:Results:paragraph6, 2:Results:paragraph7, 2:Results:paragraph8. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C50", "text": "HSPB1 restrains cytoplasmic gel/fibril states and is reduced in some affected neurons. Forced stress and postmortem chaperone loss cannot identify endogenous necessity.", "carries_number": true, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 50 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C51", "text": "Structured oligomer and RNA-binding changes alter stability splicing and aggregation. Properties change together; journal 2023 replaces the repository/preprint date.", "carries_number": false, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 51 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C52", "text": "HSP70/ATP regulate liquid shells and solidification of TDP assemblies. Proteasome challenge and nuclear material state are not sporadic ALS initiation.", "carries_number": true, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 52 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C53", "text": "DBR1-dependent RNA lariats buffer TDP toxicity. Forced expression and RNA pleiotropy; no disease survival.", "carries_number": true, "load_bearing_for": [ "SC3" ], "source_ns": [ 53 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C54", "text": "Diffuse cytoplasmic TDP predicts death; inclusion presence does not increase measured death risk. Tagged overexpression; lack of risk association does not prove inclusions protective.", "carries_number": false, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 54 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C55", "text": "Aggregation-prone frameshift is less neuron-toxic with partial functional loss. Myopathy is a different phenotype; not broad protective aggregate evidence.", "carries_number": false, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 55 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C56", "text": "Conditional loss yields progressive motor-neuron loss and glial activation. Loss of essential protein is not selective cryptic-splicing disruption alone.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 56 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C57", "text": "A cryptic PKN peptide escaping NMD can impair cognition in an expression model. Ectopic peptide toxicity is not endogenous ALS necessity.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 57 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C58", "text": "RNA-binding impairment precedes cognitive and pathological progression. Acetyl-mimic mutation is not identical to a natural acetylation state.", "carries_number": false, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 58 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C59", "text": "TDP pathological assemblies associate with nuclear-pore disruption. Cell assays and tissue association lack organismal trajectory rescue; journal 2018 replaces conference 2017.", "carries_number": false, "load_bearing_for": [ "SC3", "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": "2026-10-09", "note": "" }, { "id": "C60", "text": "Variable TDP loss signatures track nuclear pores; POM121 repair restores RNA function. Cellular repair and donor association not clinical course rescue.", "carries_number": true, "load_bearing_for": [ "SC2", "SC5" ], "source_ns": [ 60 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C61", "text": "Hydrophobic solid-like aggregates correlate with less toxicity than dynamic peripheral foci. Yeast forced expression and multifactorial sequence changes; not proof all human aggregates protect.", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 61 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph4, 1:Results:paragraph6, 1:Results:paragraph7, 1:Results:paragraph9, 1:Results:paragraph10. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C62", "text": "Artificial aggregates sequester TBPH and protect the eye from overexpression toxicity. Developmental eye context and TDP dispensability limit disease relevance.", "carries_number": false, "load_bearing_for": [ "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": "2026-10-09", "note": "" }, { "id": "C63", "text": "A chimeric splicing repressor rescues motor function and extends mouse median survival by 29 weeks in two cohorts. Neonatal AAV and knockout not sporadic initiation; litter-level randomization and delivery attrition; same Ling programme.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 63 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Materials and Methods:paragraph9, 1:Materials and Methods:paragraph10, 1:Materials and Methods:paragraph11, 1:Materials and Methods:paragraph12, 1:Materials and Methods:paragraph13, 2:Results:paragraph0, 2:Results:paragraph2, 2:Results:paragraph3, 2:Results:paragraph4, 2:Results:paragraph5, 2:Results:paragraph6. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "CSC1", "text": "Original neuropathology establishes distinct pathology classes, but prevalence alone is association and cannot assign causal function. Selected case series do not license population percentages.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 5, 6, 10, 25, 27, 29, 32 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-09", "note": "" }, { "id": "CSC2", "text": "Endogenous TDP depletion, UG/splice-site engineering, RNA-binding competent rescue, human axon/synaptic correction and chimeric-repressor rescue of motor function and survival in flies/mice converge on a functional contribution. Targets are species-specific and knockout rescue does not establish sporadic initiation.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, 17, 18, 19, 26, 28, 30, 31, 41, 43, 45, 46, 51, 52, 56, 57, 58, 60, 63 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-09", "note": "" }, { "id": "CSC3", "text": "Independent endogenous mutant-FUS lines, null comparisons, cell-restricted allele reversal and FUS lowering identify toxic gain in familial-mutant mouse contexts. Nuclear restoration and mutant removal are coupled; stage and total-dose controls matter.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 13, 14, 15, 16, 20, 21, 22, 23, 24, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 44, 47, 49, 50, 53, 54, 55, 59 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-09", "note": "" }, { "id": "CSC4", "text": "Biophysical and forced-assembly toxicity are plausible, but no selective macroscopic-aggregate intervention retaining soluble abundance and nuclear function establishes disease-relevant necessity. Aggregate-free degeneration and restricted protective sequestration are real discriminators.", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 10, 11, 14, 21, 22, 23, 25, 26, 38, 40, 43, 45, 46, 47, 48, 50, 51, 52, 54, 55, 58, 61, 62 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-09", "note": "" }, { "id": "CSC5", "text": "Postmortem proteinopathy, genotype models and rescues support plausible interacting pathways. No selective model-independent correction establishes this principal aggregate-driven dual mechanism across prespecified sporadic ALS–FTD contexts.", "carries_number": false, "load_bearing_for": [ "SC5" ], "source_ns": [ 3, 13, 16, 19, 20, 29, 33, 36, 37, 42, 44, 49, 59, 60 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-09", "note": "" }, { "id": "CH", "text": "RNA dysfunction and mutant-FUS toxicity are causal in defined systems; aggregate-driven primacy across ALS–FTD remains unproved.", "carries_number": false, "load_bearing_for": [ "SC5" ], "source_ns": [ 63, 4, 40, 24, 61 ], "verification": "verified", "verified_against": "Bounded synthesis of examined sources; score is adjudication.", "verified_on": "2026-10-09", "note": "" } ], "citation_ledger": [ { "n": 1, "citation": "Ling JP, Pletnikova O, Troncoso JC et al. TDP-43 repression of nonconserved cryptic exons is compromised in ALS-FTD. Science (New York, N.Y.). 2015.", "tier": "A", "kind": "primary", "pmid": "26250685", "doi": "10.1126/science.aab0983", "url": "https://pubmed.ncbi.nlm.nih.gov/26250685/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID26250685", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Main text:paragraph4, 1:Main text:paragraph5, 1:Main text:paragraph6, 1:Main text:paragraph7, 1:Main text:paragraph8, 1:Main text:paragraph9, 1:Main text:paragraph10, 1:Main text:paragraph11, 1:Main text:paragraph12, 1:Main text. No complete-paper or supplement audit claimed.", "carries_claims": [ "C1", "CSC2" ] }, { "n": 2, "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.", "tier": "A", "kind": "primary", "pmid": "35197628", "doi": "10.1038/s41586-022-04436-3", "url": "https://pubmed.ncbi.nlm.nih.gov/35197628/", "status_flags": [ "Erratum in: PMID 38890465" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID35197628", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C2", "CSC2" ] }, { "n": 3, "citation": "Seddighi S, Qi YA, Brown AL et al. Mis-spliced transcripts generate de novo proteins in TDP-43-related ALS/FTD. Science translational medicine. 2024.", "tier": "A", "kind": "primary", "pmid": "38277467", "doi": "10.1126/scitranslmed.adg7162", "url": "https://pubmed.ncbi.nlm.nih.gov/38277467/", "status_flags": [ "Update of: PMID 36747793" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID38277467", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C3", "CSC2", "CSC5" ] }, { "n": 4, "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.", "tier": "A", "kind": "primary", "pmid": "36927019", "doi": "10.1126/science.abq5622", "url": "https://pubmed.ncbi.nlm.nih.gov/36927019/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID36927019", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:A GU-motif confers TDP-43 binding-dependent maturation of stathmin-2 pre-mRNA, 1:TDP-43 binding sterically blocks cryptic splicing and polyadenylation of STMN2, 2:Genomic disruption of exon 2a cryptic splice site protects against misprocessing, 6:rASOs restore axonal regeneration capacity in TDP-43 deficient motor neurons, 7:rASO-mediated restoration of Stmn2 pre-mRNA processing in the mammalian CNS. No complete-paper or supplement audit claimed.", "carries_claims": [ "C4", "CSC2", "CH" ] }, { "n": 5, "citation": "Irwin KE, Jasin P, Braunstein KE et al. A fluid biomarker reveals loss of TDP-43 splicing repression in presymptomatic ALS-FTD. Nature medicine. 2024.", "tier": "A", "kind": "primary", "pmid": "38278991", "doi": "10.1038/s41591-023-02788-5", "url": "https://pubmed.ncbi.nlm.nih.gov/38278991/", "status_flags": [ "Update of: PMID 36789434", "Erratum in: PMID 38580817" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID38278991", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C5", "CSC1", "CSC2" ] }, { "n": 6, "citation": "Prudencio M, Humphrey J, Pickles S et al. Truncated stathmin-2 is a marker of TDP-43 pathology in frontotemporal dementia. The Journal of clinical investigation. 2020.", "tier": "A", "kind": "primary", "pmid": "32790644", "doi": "10.1172/JCI139741", "url": "https://pubmed.ncbi.nlm.nih.gov/32790644/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID32790644", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C6", "CSC1", "CSC2" ] }, { "n": 7, "citation": "Ma XR, Prudencio M, Koike Y et al. TDP-43 represses cryptic exon inclusion in the FTD-ALS gene UNC13A. Nature. 2022.", "tier": "A", "kind": "primary", "pmid": "35197626", "doi": "10.1038/s41586-022-04424-7", "url": "https://pubmed.ncbi.nlm.nih.gov/35197626/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID35197626", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Main:paragraph2, 0:Main:paragraph5, 0:Main:paragraph6, 0:Main:paragraph18, 0:Main:paragraph19, 0:Main:paragraph20, 0:Main:paragraph21. No complete-paper or supplement audit claimed.", "carries_claims": [ "C7", "CSC2" ] }, { "n": 8, "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.", "tier": "A", "kind": "primary", "pmid": "30643292", "doi": "10.1038/s41593-018-0300-4", "url": "https://pubmed.ncbi.nlm.nih.gov/30643292/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID30643292", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C8", "CSC2" ] }, { "n": 9, "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.", "tier": "A", "kind": "primary", "pmid": "30643298", "doi": "10.1038/s41593-018-0293-z", "url": "https://pubmed.ncbi.nlm.nih.gov/30643298/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID30643298", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C9", "CSC2" ] }, { "n": 10, "citation": "Spence H, Waldron FM, Saleeb RS et al. RNA aptamer reveals nuclear TDP-43 pathology is an early aggregation event that coincides with STMN-2 cryptic splicing and precedes clinical manifestation in ALS. Acta neuropathologica. 2024.", "tier": "A", "kind": "primary", "pmid": "38443601", "doi": "10.1007/s00401-024-02705-1", "url": "https://pubmed.ncbi.nlm.nih.gov/38443601/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID38443601", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C10", "CSC1", "CSC2", "CSC4" ] }, { "n": 11, "citation": "Huang WP, Ellis BCS, Hodgson RE et al. Stress-induced TDP-43 nuclear condensation causes splicing loss of function and STMN2 depletion. Cell reports. 2024.", "tier": "A", "kind": "primary", "pmid": "38941189", "doi": "10.1016/j.celrep.2024.114421", "url": "https://pubmed.ncbi.nlm.nih.gov/38941189/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID38941189", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C11", "CSC2", "CSC4" ] }, { "n": 12, "citation": "Krus KL, Strickland A, Yamada Y et al. Loss of Stathmin-2, a hallmark of TDP-43-associated ALS, causes motor neuropathy. Cell reports. 2022.", "tier": "A", "kind": "primary", "pmid": "35767949", "doi": "10.1016/j.celrep.2022.111001", "url": "https://pubmed.ncbi.nlm.nih.gov/35767949/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID35767949", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C12", "CSC2" ] }, { "n": 13, "citation": "Wang W, Wang L, Lu J et al. The inhibition of TDP-43 mitochondrial localization blocks its neuronal toxicity. Nature medicine. 2016.", "tier": "A", "kind": "primary", "pmid": "27348499", "doi": "10.1038/nm.4130", "url": "https://pubmed.ncbi.nlm.nih.gov/27348499/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID27348499", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C13", "CSC3", "CSC5" ] }, { "n": 14, "citation": "Mann JR, Gleixner AM, Mauna JC et al. RNA Binding Antagonizes Neurotoxic Phase Transitions of TDP-43. Neuron. 2019.", "tier": "A", "kind": "primary", "pmid": "30826182", "doi": "10.1016/j.neuron.2019.01.048", "url": "https://pubmed.ncbi.nlm.nih.gov/30826182/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID30826182", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C14", "CSC3", "CSC4" ] }, { "n": 15, "citation": "Walker AK, Spiller KJ, Ge G et al. Functional recovery in new mouse models of ALS/FTLD after clearance of pathological cytoplasmic TDP-43. Acta neuropathologica. 2015.", "tier": "A", "kind": "primary", "pmid": "26197969", "doi": "10.1007/s00401-015-1460-x", "url": "https://pubmed.ncbi.nlm.nih.gov/26197969/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID26197969", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C15", "CSC2", "CSC3" ] }, { "n": 16, "citation": "Becker LA, Huang B, Bieri G et al. Therapeutic reduction of ataxin-2 extends lifespan and reduces pathology in TDP-43 mice. Nature. 2017.", "tier": "A", "kind": "primary", "pmid": "28405022", "doi": "10.1038/nature22038", "url": "https://pubmed.ncbi.nlm.nih.gov/28405022/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID28405022", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C16", "CSC3", "CSC5" ] }, { "n": 17, "citation": "Joseph BJ, Marshall KA, Harley P et al. TDP-43-dependent mis-splicing of KCNQ2 triggers intrinsic neuronal hyperexcitability in ALS/FTD. Nature neuroscience. 2025.", "tier": "A", "kind": "primary", "pmid": "41174170", "doi": "10.1038/s41593-025-02096-w", "url": "https://pubmed.ncbi.nlm.nih.gov/41174170/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID41174170", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C17", "CSC2" ] }, { "n": 18, "citation": "Bryce-Smith S, Brown AL, Chien MZYJ et al. TDP-43 loss induces cryptic polyadenylation in ALS/FTD. Nature neuroscience. 2025.", "tier": "A", "kind": "primary", "pmid": "41120751", "doi": "10.1038/s41593-025-02050-w", "url": "https://pubmed.ncbi.nlm.nih.gov/41120751/", "status_flags": [ "Update of: PMID 38313254" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID41120751", "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": "Coyne AN, Baskerville V, Zaepfel BL et al. Nuclear accumulation of CHMP7 initiates nuclear pore complex injury and subsequent TDP-43 dysfunction in sporadic and familial ALS. Science translational medicine. 2021.", "tier": "A", "kind": "primary", "pmid": "34321318", "doi": "10.1126/scitranslmed.abe1923", "url": "https://pubmed.ncbi.nlm.nih.gov/34321318/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID34321318", "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", "CSC5" ] }, { "n": 20, "citation": "Guo L, Kim HJ, Wang H et al. Nuclear-Import Receptors Reverse Aberrant Phase Transitions of RNA-Binding Proteins with Prion-like Domains. Cell. 2018.", "tier": "A", "kind": "primary", "pmid": "29677512", "doi": "10.1016/j.cell.2018.03.002", "url": "https://pubmed.ncbi.nlm.nih.gov/29677512/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID29677512", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C20", "CSC3", "CSC5" ] }, { "n": 21, "citation": "Hofweber M, Hutten S, Bourgeois B et al. Phase Separation of FUS Is Suppressed by Its Nuclear Import Receptor and Arginine Methylation. Cell. 2018.", "tier": "A", "kind": "primary", "pmid": "29677514", "doi": "10.1016/j.cell.2018.03.004", "url": "https://pubmed.ncbi.nlm.nih.gov/29677514/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID29677514", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C21", "CSC3", "CSC4" ] }, { "n": 22, "citation": "Mackenzie IR, Nicholson AM, Sarkar M et al. TIA1 Mutations in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Promote Phase Separation and Alter Stress Granule Dynamics. Neuron. 2017.", "tier": "A", "kind": "primary", "pmid": "28817800", "doi": "10.1016/j.neuron.2017.07.025", "url": "https://pubmed.ncbi.nlm.nih.gov/28817800/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID28817800", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C22", "CSC3", "CSC4" ] }, { "n": 23, "citation": "Fang MY, Markmiller S, Vu AQ et al. Small-Molecule Modulation of TDP-43 Recruitment to Stress Granules Prevents Persistent TDP-43 Accumulation in ALS/FTD. Neuron. 2019.", "tier": "A", "kind": "primary", "pmid": "31272829", "doi": "10.1016/j.neuron.2019.05.048", "url": "https://pubmed.ncbi.nlm.nih.gov/31272829/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID31272829", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C23", "CSC3", "CSC4" ] }, { "n": 24, "citation": "Korben VA, Lyashchenko AK, Blanco-Redondo B et al. Antisense oligonucleotide silencing of FUS expression as a therapeutic approach in amyotrophic lateral sclerosis. Nature medicine. 2022.", "tier": "A", "kind": "primary", "pmid": "35075293", "doi": "10.1038/s41591-021-01615-z", "url": "https://pubmed.ncbi.nlm.nih.gov/35075293/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID35075293", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph3, 1:Results:paragraph36, 1:Results:paragraph49, 1:Results:paragraph52, 1:Results:paragraph53, 1:Results:paragraph59. No complete-paper or supplement audit claimed.", "carries_claims": [ "C24", "CSC3", "CH" ] }, { "n": 25, "citation": "Arseni D, Hasegawa M, Murzin AG et al. Structure of pathological TDP-43 filaments from ALS with FTLD. Nature. 2022.", "tier": "A", "kind": "primary", "pmid": "34880495", "doi": "10.1038/s41586-021-04199-3", "url": "https://pubmed.ncbi.nlm.nih.gov/34880495/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID34880495", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C25", "CSC1", "CSC4" ] }, { "n": 26, "citation": "Conicella AE, Dignon GL, Zerze GH et al. TDP-43 α-helical structure tunes liquid-liquid phase separation and function. Proceedings of the National Academy of Sciences of the United States of America. 2020.", "tier": "A", "kind": "primary", "pmid": "32132204", "doi": "10.1073/pnas.1912055117", "url": "https://pubmed.ncbi.nlm.nih.gov/32132204/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID32132204", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C26", "CSC2", "CSC4" ] }, { "n": 27, "citation": "Arai T, Hasegawa M, Akiyama H et al. TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochemical and biophysical research communications. 2006.", "tier": "A", "kind": "primary", "pmid": "17084815", "doi": "10.1016/j.bbrc.2006.10.093", "url": "https://pubmed.ncbi.nlm.nih.gov/17084815/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID17084815", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C27", "CSC1" ] }, { "n": 28, "citation": "Belchikov N, Hu W, Fan L et al. A single-cell, long-read, isoform-resolved case-control study of FTD reveals cell-type-specific and broad splicing dysregulation in human brain. Cell reports. 2025.", "tier": "A", "kind": "primary", "pmid": "40913764", "doi": "10.1016/j.celrep.2025.116198", "url": "https://pubmed.ncbi.nlm.nih.gov/40913764/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID40913764", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C28", "CSC2" ] }, { "n": 29, "citation": "Mackenzie IR, Munoz DG, Kusaka H et al. Distinct pathological subtypes of FTLD-FUS. 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