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.
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:#ef9a9aNo linked papers recorded for this hypothesis yet.
Median TPM across 13 brain regions for FUS from GTEx v10.
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.
No resource usage or linked notebooks recorded for this hypothesis yet.
| 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 |