ALS-linked proteostasis stress lowers effective GPX4 reserve in vulnerable motor neurons, allowing oxidized phospholipids to cross a ferroptotic death threshold. Restoring GPX4 activity or glutathione availability should rescue motor-neuron survival more strongly than generic antioxidants.
Curated pathway from expert analysis
flowchart TD
A["ALS proteostasis stress"] --> B["GPX4 reserve depletion"]
A --> C["Glutathione depletion"]
B --> D["Oxidized phospholipid accumulation"]
C --> D
D --> E{"Ferroptotic threshold crossed?"}
E -->|" Yes "| F["Ferroptosis activation"]
F --> G["Motor neuron death"]
E -->|" No "| H["Motor neuron survival"]
B --> I["GPX4 activity restoration"]
C --> J["Glutathione supplementation"]
I --> K["Neuroprotection"]
J --> K
K -->|" Rescues "| G
style A fill:#ffd54f,color:#0d0d1a
style B fill:#4fc3f7,color:#0d0d1a
style C fill:#4fc3f7,color:#0d0d1a
style D fill:#4fc3f7,color:#0d0d1a
style E fill:#ef5350,color:#0d0d1a
style F fill:#ef5350,color:#0d0d1a
style G fill:#ef5350,color:#0d0d1a
style I fill:#81c784,color:#0d0d1a
style J fill:#81c784,color:#0d0d1a
style K fill:#81c784,color:#0d0d1aNo linked papers recorded for this hypothesis yet.
Median TPM across 13 brain regions for GPX4 from GTEx v10.
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 GPX4.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
No resource usage or linked notebooks recorded for this hypothesis yet.