Convergence hypothesis: NRF2 (NFE2L2) is the central transcriptional regulator whose failure explains parallel proteostatic collapse in both PD and AD, making it a high-priority cross-disease target.
PD-specific mechanism: NRF2 regulates ARE-containing genes (HMOX1, NQO1, GCLC, GSTM1) that detoxify reactive oxygen species generated by mitochondrial dysfunction and neuromelanin iron accumulation. In PD, KEAP1 releases NRF2 in early disease to compensate, but chronic oxidative stress (elevated 4-HNE, 8-OHdG in substantia nigra) eventually overwhelms this response, leading to NRF2 nuclear translocation failure. The resulting proteasome (PSMB5, PSMD4) and autophagy (LAMP2A, GABARAP) failure accelerates α-synuclein aggregation.
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Curated pathway diagram from expert analysis
flowchart TD
A["Oxidative Stress
PD SNCA and AD Abeta Tau Burden"]
B["KEAP1 NRF2 Switch
NFE2L2 Stabilization"]
C["ARE Gene Program
HMOX1 NQO1 GCLC GSTM1"]
D["SQSTM1 Autophagy Coupling
Proteostatic Clearance"]
E["Chronic Stress NRF2 Failure
Antioxidant Exhaustion"]
F["Proteasome and Autophagy Collapse
Aggregate Accumulation"]
G["PD AD Shared Vulnerability
Proteostatic Convergence"]
A --> B
B --> C
C --> D
A --> E
E --> F
D -.->|"when insufficient"| F
F --> G
style B fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style G fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
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Freshness score = exp(-age×ln2/5): halves every 5 years. Green >0.6, Amber 0.3–0.6, Red <0.3.
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No DepMap CRISPR Chronos data found for NFE2L2,KEAP1,HMOX1,SQSTM1,PSMB5.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
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Run scripts/backfill_clinvar_variants.py to fetch P/LP/VUS variants.
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