Dying or stressed neurons release alpha-synuclein and DAMPs that activate microglia, which then generate superoxide through NOX2 and amplify TNF, IL1B, and NF-kB signaling. That extracellular ROS and cytokine field injures neighboring neurons, causing more aggregate release and renewed microglial activation. This best explains tissue-level spread and persistence rather than the earliest intracellular trigger.
Curated pathway from expert analysis
flowchart TD
A["CYBB; NCF1; NCF2; RELA; NLRP3<br/>Primary Target"]
B["Biological Process 1<br/>Mechanistic Step A"]
C["Biological Process 2<br/>Mechanistic Step B"]
D["Output Phenotype<br/>Disease Effect"]
A --> B
B --> C
C --> D
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style D fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9aNo linked papers recorded for this hypothesis yet.
No curated PDB or AlphaFold mapping for CYBB; yet. Search RCSB →
Median TPM across 13 brain regions for CYBB; NCF1; NCF2; RELA; NLRP3 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 CYBB; NCF1; NCF2; RELA; NLRP3.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF microglial NOX2 is selectively inhibited (pharmacologically with GKT137831 at 10 mg/kg/day i.p. or genetically via Cx3cr1-Cre conditional knockout of Cybb) in a mouse model of alpha-synuclein propa | Significant reduction in outward spread of oxidative DNA damage markers (8-OHdG+) and mitochondrial superoxide (mitoSOX) beyond the primary injection site, with | — no observation — | pending | 0.65 |
| IF NLRP3 inflammasome is genetically deleted (Nlrp3−/−) or pharmacologically inhibited (MCC950, 10 mg/kg/day i.p.) to interrupt the ROS-inflammasome feedback loop in a localized viral vector model of | Significant reduction in plasma IL-1β levels (ELISA, expected decrease from ~80 pg/mL in WT-vehicle to ≤40 pg/mL in Nlrp3−/− or MCC950-treated) and reduced micr | — no observation — | pending | 0.55 |