C9ORF72 autophagy-lysosome collapse across ALS and FTD
🧪 Overview
Shared mechanism across ALS, FTD: C9ORF72 repeat expansion creates toxic RNA/dipeptide stress while also weakening vesicle trafficking, autophagy, and basal mitophagy. The same upstream repeat biology can manifest as motor-neuron ALS, cortical FTD, or mixed ALS-FTD depending on cell-type stress thresholds.
Falsifiable prediction: Correcting C9ORF72 repeat RNA with ASO should restore basal mitophagy flux by at least 20% and reduce p62-positive autophagy backlog in both motor neurons and frontotemporal cortical neurons from the same carrier lines.
Proposed experiment: Generate paired motor neuron and cortical neuron cultures from C9ORF72 carriers; apply repeat-targeting ASO; measure RNA foci, DPR proteins, LC3/p62 flux, basal mitophagy reporters, TDP-43 mislocalization, and cell-type survival.
Cross-disease confidence rationale: Two independent discovery papers identify the ALS-FTD repeat, with newer mitophagy evidence.
Internal SciDEX support: SciDEX support query found 55 matching hypotheses across 5 disease labels, including 55 with debate_count > 0.
🧬 Mechanism
Auto-built from this analysis's top knowledge-graph edges.
graph TD
h_cross_synth_c9orf72_aut["h-cross-synth-c9orf72-autophagy-lysosome"] -->|proposes shared me| C9ORF72["C9ORF72"]
C9ORF72_1["C9ORF72"] -->|cross disease mech| ALS["ALS"]
C9ORF72_2["C9ORF72"] -->|cross disease mech| FTD["FTD"]
style h_cross_synth_c9orf72_aut fill:#4fc3f7,stroke:#333,color:#000
style C9ORF72 fill:#4fc3f7,stroke:#333,color:#000
style C9ORF72_1 fill:#4fc3f7,stroke:#333,color:#000
style ALS fill:#ef5350,stroke:#333,color:#000
style C9ORF72_2 fill:#4fc3f7,stroke:#333,color:#000
style FTD fill:#ef5350,stroke:#333,color:#000⚖️ Evidence
🏥 Translation
🧬 3D Protein Structure — C9ORF72
No curated PDB or AlphaFold mapping for C9ORF72 yet. Search RCSB →
💉 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 C9ORF72.
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 |
|---|---|---|---|---|
| Correcting C9ORF72 repeat RNA with ASO should restore basal mitophagy flux by at least 20% and reduce p62-positive autophagy backlog in both motor neurons and frontotemporal cortical neurons from the | If this mechanism is real, then Correcting C9ORF72 repeat RNA with ASO should restore basal mitophagy flux by at least 20% and reduce p62-positive autophagy bac | — no observation — | pending | 0.83 |
▸Metadatasource: v1_phase_c_backfill · origin_type: cross_disease_synthesis
| source | v1_phase_c_backfill |
| origin_type | cross_disease_synthesis |
| _schema_version | 1 |