The same signal may be beneficial early and damaging late. Testing proteasome shuttle failure with autophagy flux rescue should reveal a disease-stage interaction and define when intervention is protective versus counterproductive.
Curated pathway from expert analysis
flowchart TD
A["proteasome shuttle failure<br/>Hypothesis Target"]
B["Autophagy<br/>Cited Mechanism"]
C["Cellular Response<br/>Stress or Clearance Change"]
D["Neural Circuit Effect<br/>Synapse/Glia Vulnerability"]
E["ALS<br/>Disease-Relevant Outcome"]
A --> B
B --> C
C --> D
D --> E
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style B fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style E fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9aNo curated PDB or AlphaFold mapping for PROTEASOME yet. Search RCSB →
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 proteasome shuttle failure.
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 shuttle failure is the proximal lesion, THEN proteasome reporter clearance will slow by >=25% before motor-neuron viability drops by 10% in UBQLN2 mutant cultures. | Proteasome reporter half-life increases >=25% at a pre-viability-loss timepoint. | — no observation — | pending | 0.62 |
| IF proteasome shuttle failure defines the UBQLN2 therapeutic window, THEN early autophagy-flux rescue will lower insoluble UBQLN2 by >=30%, but delayed rescue after aggregate maturation will lower it | Early rescue reduces insoluble UBQLN2 >=30%; delayed rescue reduces insoluble UBQLN2 <10%. | — no observation — | pending | 0.58 |