G2019S basal RAB10 phosphorylation elevation may be secondary; true pathogenic driver is amplified stress-response signaling. Partial LRRK2 inhibition sufficient to normalize stress-induced spikes while preserving necessary baseline functions. LRRK2 knockout mice viability supports non-essential baseline hypothesis. Age-dependent neurodegeneration in knock-in mice suggests stress-dependent pathology rather than chronic baseline elevation.
Curated pathway from expert analysis
flowchart TD
A["LRRK2 Mutation<br/>Gain of Function Kinase"]
B["Amplified Signaling<br/>Not Baseline Activity"]
C["Pathological Signaling<br/>Threshold Exceeded"]
D["Neuronal Vulnerability<br/>vs Resilience"]
E["Lysosomal Dysfunction<br/>Autophagy Impairment"]
F["Therapeutic Window<br/>Exists"]
G["Signal Reduction<br/>as Intervention Target"]
A --> B
B --> C
C --> D
D --> E
B --> F
F --> G
G --> E
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style E fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style F fill:#1b5e20,stroke:#a5d6a7,color:#a5d6a7No linked papers recorded for this hypothesis yet.
Median TPM across 13 brain regions for LRRK2 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 LRRK2.
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 partial LRRK2 kinase inhibition is sufficient to normalize amplified stress-induced signaling while preserving baseline functions, THEN low-dose MLi-2 treatment (10 mg/kg/day, achieving ~50% kinase | Low-dose MLi-2 (partial inhibition) and LRRK2 KO will produce statistically equivalent neuroprotection (p>0.05 between these groups) with normalized stress-indu | — no observation — | pending | 0.55 |
| IF G2019S LRRK2 pathogenicity is driven by amplified stress-response signaling (not baseline RAB10 phosphorylation elevation), THEN acute neuroinflammatory stress challenge using systemic LPS (5 mg/kg | G2019S KI mice will show significantly amplified RAB10 phosphorylation responses (p<0.01) and exacerbated neurodegeneration following repeated LPS stress, where | — no observation — | pending | 0.65 |