C9orf72 Hexanucleotide Repeat Dipeptide Repeat Proteins Inhibit Nucleocytoplasmic Transport
🧪 Overview
C9orf72 repeat transcripts undergo non-ATG translation producing DPRs (poly-GA, poly-GR, poly-PR) that sequester nucleocytoplasmic transport factors (RanGAP1, NUP205, TPR), causing nuclear envelope rupture and transport impairment. This represents the most mechanistically detailed hypothesis for C9orf72-ALS/FTD, with compelling evidence from multiple laboratories and promising therapeutic candidates (KPT-276, importin-β agonists). However, causality remains debated—DPR accumulation may be a consequence rather than driver. The hypothesis faces challenges from variable DPR-disease severity correlation and multiple parallel pathogenic mechanisms (C9orf72 haploinsufficiency, RNA foci, tidal RNAs). The Skeptic revised confidence to 0.72, noting that poly-GA inclusions show minimal correlation with disease severity.
🧬 Mechanism
Curated pathway from expert analysis
flowchart TD
A["C9orf72 Hexanucleotide<br/>Repeat Expansion"]
B["Dipeptide Repeat Proteins<br/>Poly-GA-PA-PR-Pro"]
C["NUP98 Nuclear Pore<br/>Impairment"]
D["Nucleocytoplasmic<br/>Transport Blocked"]
E["mRNA Export<br/>Deficit"]
F["Proteostatic Stress<br/>and Aggregation"]
G["NUP98 as Therapeutic<br/>Target"]
A --> B
B --> C
C --> D
D --> E
E --> F
F --> G
style A fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style F fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style G fill:#1b5e20,stroke:#a5d6a7,color:#a5d6a7⚖️ Evidence
No linked papers recorded for this hypothesis yet.
🏥 Translation
🧬 3D Protein Structure — NUP98
No curated PDB or AlphaFold mapping for NUP98 yet. Search RCSB →
🧠 GTEx v10 Brain ExpressionJSON
Median TPM across 13 brain regions for NUP98 from GTEx v10.
💉 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 NUP98.
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 |
|---|---|---|---|---|
| IF we stratify C9orf72-ALS/FTD patients by cerebrospinal fluid DPR levels (poly-GR top quartile vs. bottom quartile) at baseline, THEN the high DPR group will exhibit significantly greater impairment | High DPR group will show ≥35% higher nuclear hnRNP A1 accumulation (indicating export impairment) compared to low DPR group, with correlation strength r ≥ 0.5 b | — no observation — | pending | 0.58 |
| IF C9orf72-ALS patient-derived motor neurons are treated with antisense oligonucleotides that selectively reduce DPR protein levels (poly-GA, poly-GR, poly-PR) without altering C9orf72 mRNA or RNA foc | Nuclear import rate will increase by ≥40% in DPR-reduced neurons relative to baseline, with no change in total C9orf72 transcript levels | — no observation — | pending | 0.65 |
▸Metadatasource: v1_phase_c_backfill · origin_type: debate_synthesizer
| source | v1_phase_c_backfill |
| origin_type | debate_synthesizer |
| _schema_version | 1 |