TDP-43 RNA-proteostasis failure across ALS, FTD, and AD/LATE
🧪 Overview
Shared mechanism across ALS, FTD, AD/LATE: Nuclear TDP-43 loss impairs RNA splicing and axonal maintenance; the same mislocalized protein forms ubiquitinated cytoplasmic aggregates in ALS/FTD and limbic TDP-43 pathology in AD/LATE, producing disease-specific vulnerable cell loss through a shared RNA-proteostasis bottleneck.
Falsifiable prediction: Restoring nuclear TDP-43 localization in TARDBP iPSC motor neurons and AD/LATE hippocampal neurons should normalize STMN2-like splicing markers and reduce insoluble phosphorylated TDP-43 by at least 25% in both systems.
Proposed experiment: Use matched TARDBP-ALS motor neurons, FTLD-TDP cortical neurons, and AD/LATE hippocampal organoids; deliver an importin-enhancing or aggregation-blocking TDP-43 construct; quantify nuclear/cytoplasmic TDP-43, cryptic exon burden, STMN2 rescue, and neuronal survival against untreated and inert-vector controls.
Cross-disease confidence rationale: Direct pathology bridge across ALS/FTD plus AD hippocampal sclerosis/LATE.
Internal SciDEX support: SciDEX support query found 48 matching hypotheses across 8 disease labels, including 48 with debate_count > 0.
🧬 Mechanism
Auto-built from this analysis's top knowledge-graph edges.
graph TD
TARDBP_MUTATIONS["TARDBP MUTATIONS"] -->|causes| ALS_FTD["ALS/FTD"]
TARDBP["TARDBP"] -->|cross disease mech| ALS["ALS"]
TARDBP_1["TARDBP"] -->|cross disease mech| FTD["FTD"]
TARDBP_2["TARDBP"] -->|cross disease mech| AD_LATE["AD/LATE"]
h_cross_synth_tdp43_rna_p["h-cross-synth-tdp43-rna-proteostasis"] -->|proposes shared me| TARDBP_3["TARDBP"]
style TARDBP_MUTATIONS fill:#ce93d8,stroke:#333,color:#000
style ALS_FTD fill:#ef5350,stroke:#333,color:#000
style TARDBP fill:#4fc3f7,stroke:#333,color:#000
style ALS fill:#ef5350,stroke:#333,color:#000
style TARDBP_1 fill:#4fc3f7,stroke:#333,color:#000
style FTD fill:#ef5350,stroke:#333,color:#000
style TARDBP_2 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_3 fill:#4fc3f7,stroke:#333,color:#000⚖️ Evidence
🏥 Translation
🧬 3D Protein Structure — TARDBP
💉 Clinical Trials
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 TARDBP.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
🏆 Tournament
🏆 Arenas / Elo
📊 Market Indicators
💾 Resource Usage
No resource usage or linked notebooks recorded for this hypothesis yet.
🔮 Predictions
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| Restoring nuclear TDP-43 localization in TARDBP iPSC motor neurons and AD/LATE hippocampal neurons should normalize STMN2-like splicing markers and reduce insoluble phosphorylated TDP-43 by at least 2 | If this mechanism is real, then Restoring nuclear TDP-43 localization in TARDBP iPSC motor neurons and AD/LATE hippocampal neurons should normalize STMN2-like s | — no observation — | pending | 0.86 |
▸Metadatasource: v1_phase_c_backfill · origin_type: cross_disease_synthesis
| source | v1_phase_c_backfill |
| origin_type | cross_disease_synthesis |
| _schema_version | 1 |