Shared mechanism across ALS, FTD: Low-complexity RNA-binding proteins normally form reversible stress granules, but ALS/FTD-linked variants push granules toward persistent phase-separated assemblies that trap TDP-43 and impair RNA homeostasis. Different RBPs converge on the same granule-hardening mechanism.
Falsifiable prediction: Lowering TIA1 or hnRNPA1 granule persistence should shorten stress-granule half-life by at least 30% and reduce cytoplasmic TDP-43 recruitment in both ALS motor neurons and FTD cortical neurons carrying RBP/TDP-43 stress.
Proposed experiment: Introduce TIA1, HNRNPA1, or HNRNPA2B1 variants into isogenic motor and cortical neurons; apply ISR modulation or targeted RBP knockdown; image granule dynamics, FRAP recovery, TDP-43 recruitment, cryptic exon burden, and survival after stress.
Cross-disease confidence rationale: Direct TIA1 ALS/FTD evidence plus hnRNP prion-like domain ALS mechanism.
Internal SciDEX support: SciDEX support query found 41 matching hypotheses across 6 disease labels, including 41 with debate_count > 0.
Auto-built from this analysis's top knowledge-graph edges.
graph TD
GBA1_mutations["GBA1 mutations"] -->|increases risk| PD["PD"]
TREM2_R47H_variant["TREM2 R47H variant"] -->|increases risk| Ad["Ad"]
alpha_synuclein_fibrils["alpha-synuclein fibrils"] -->|activates| NLRP3_Inflammasome["NLRP3 Inflammasome"]
TFEB_overexpression["TFEB overexpression"] -.->|inhibits| tau_A__pathology["tau/Aβ pathology"]
TARDBP_MUTATIONS["TARDBP MUTATIONS"] -->|causes| ALS_FTD["ALS/FTD"]
TDP_43_INCLUSIONS["TDP-43 INCLUSIONS"] -->|associated with| ALS_FTD_1["ALS/FTD"]
NfL_reduction["NfL reduction"] -->|biomarker for| als["als"]
TARDBP["TARDBP"] -->|cross disease mech| ALS["ALS"]
TARDBP_2["TARDBP"] -->|cross disease mech| FTD["FTD"]
TARDBP_3["TARDBP"] -->|cross disease mech| AD_LATE["AD/LATE"]
h_cross_synth_tdp43_rna_p["h-cross-synth-tdp43-rna-proteostasis"] -->|proposes shared me| TARDBP_4["TARDBP"]
SNCA["SNCA"] -->|cross disease mech| PD_5["PD"]
style GBA1_mutations fill:#ce93d8,stroke:#333,color:#000
style PD fill:#ef5350,stroke:#333,color:#000
style TREM2_R47H_variant fill:#ce93d8,stroke:#333,color:#000
style Ad fill:#ef5350,stroke:#333,color:#000
style alpha_synuclein_fibrils fill:#4fc3f7,stroke:#333,color:#000
style NLRP3_Inflammasome fill:#ce93d8,stroke:#333,color:#000
style TFEB_overexpression fill:#4fc3f7,stroke:#333,color:#000
style tau_A__pathology fill:#4fc3f7,stroke:#333,color:#000
style TARDBP_MUTATIONS fill:#ce93d8,stroke:#333,color:#000
style ALS_FTD fill:#ef5350,stroke:#333,color:#000
style TDP_43_INCLUSIONS fill:#4fc3f7,stroke:#333,color:#000
style ALS_FTD_1 fill:#ef5350,stroke:#333,color:#000
style NfL_reduction fill:#ce93d8,stroke:#333,color:#000
style als fill:#ef5350,stroke:#333,color:#000
style TARDBP fill:#4fc3f7,stroke:#333,color:#000
style ALS fill:#ef5350,stroke:#333,color:#000
style TARDBP_2 fill:#4fc3f7,stroke:#333,color:#000
style FTD fill:#ef5350,stroke:#333,color:#000
style TARDBP_3 fill:#4fc3f7,stroke:#333,color:#000
style AD_LATE fill:#ef5350,stroke:#333,color:#000
style h_cross_synth_tdp43_rna_p fill:#4fc3f7,stroke:#333,color:#000
style TARDBP_4 fill:#4fc3f7,stroke:#333,color:#000
style SNCA fill:#4fc3f7,stroke:#333,color:#000
style PD_5 fill:#ef5350,stroke:#333,color:#000No curated PDB or AlphaFold mapping for TIA1;HNRNPA1;HNRNPA2B1 yet. Search RCSB →
No clinical trials data linked to this hypothesis yet.
No curated ClinVar variants loaded for this hypothesis.
Run scripts/backfill_clinvar_variants.py to fetch P/LP/VUS variants.
No DepMap CRISPR Chronos data found for TIA1;HNRNPA1;HNRNPA2B1.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
No resource usage or linked notebooks recorded for this hypothesis yet.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| Lowering TIA1 or hnRNPA1 granule persistence should shorten stress-granule half-life by at least 30% and reduce cytoplasmic TDP-43 recruitment in both ALS motor neurons and FTD cortical neurons carryi | If this mechanism is real, then Lowering TIA1 or hnRNPA1 granule persistence should shorten stress-granule half-life by at least 30% and reduce cytoplasmic TDP- | — no observation — | pending | 0.74 |