Small-Molecule FUS Nuclear Import Correctors Rescue Motor Neuron Toxicity
🧪 Overview
ALS-linked FUS mutations (P525L, R521C) impair nuclear import via karyopherin-β2 (Transportin-1), causing cytoplasmic accumulation and splicing dysregulation. A compound screen for nuclear import correctors is proposed. Critical weaknesses include lack of validated small-molecule PPI modulators for FUS-Transportin-1, insufficient correlation between N/C ratio and functional splicing restoration, and stress granule pathology that may persist even with partial nuclear import restoration.
🧬 Mechanism
Curated pathway from expert analysis
flowchart TD
A["FUS Mutation<br/>RNA-binding Protein Misfolding"]
B["Cytoplasmic<br/>Inclusion Formation"]
C["Mitochondrial<br/>Dysfunction"]
D[" oxidative Stress<br/>ROS Accumulation"]
E["NCOA4-mediated<br/>Ferritinophagy"]
F["Labile Iron<br/>Pool Expansion"]
G["Lipid Peroxidation<br/>GPX4 Overwhelmed"]
H["Ferroptotic<br/>Motor Neuron Death"]
A --> B
B --> C
C --> D
D --> E
E --> F
F --> G
G --> H
style A fill:#6a1b9a,stroke:#ce93d8,color:#ce93d8
style H fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a⚖️ Evidence
No linked papers recorded for this hypothesis yet.
🏥 Translation
🧬 3D Protein Structure — FUS
🧠 GTEx v10 Brain ExpressionJSON
Median TPM across 13 brain regions for FUS 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 FUS.
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 iPSC-derived motor neurons from ALS patients carrying FUS P525L or R521C mutations are treated with a Transportin-1 pathway activator for 48 hours, THEN the nuclear-to-cytoplasmic FUS ratio will in | Nuclear/cytoplasmic FUS ratio ≥1.5-fold increase AND ≥60% splicing correction (≥508/847 events normalized to isogenic control levels) | — no observation — | pending | 0.55 |
| IF iPSC-derived motor neurons from ALS patients with FUS P525L or R521C mutations are treated with nuclear import corrector compounds for 7 days, THEN stress granule area per cell will decrease by ≥50 | Stress granule area normalized to cell area ≤50% of vehicle AND viable motor neuron count ≥140% of vehicle after 7 days | — no observation — | pending | 0.45 |
▸Metadatasource: v1_phase_c_backfill · origin_type: debate_synthesizer
| source | v1_phase_c_backfill |
| origin_type | debate_synthesizer |
| _schema_version | 1 |