The most supported model is that pathogenic G2019S shifts the basal catalytic set-point upward, producing higher baseline phospho-Rab output while leaving the core lysosomal volume-sensing response architecture largely intact. In this view, mutant cells begin from a higher activity floor, and the key experimental discriminator is whether baseline-normalized EC50, slope, or Emax materially increase during graded swelling.
Curated pathway from expert analysis
flowchart TD
A["LRRK2<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:#ef9a9aMedian 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.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF G2019S and WT cells are treated with graded concentrations of osmotic lysosomal stressors (mannitol, sucrose, or nigericin) for 2-24 hours, THEN the baseline-normalized dose-response curve for phos | Normalized EC50, Emax, and Hill slope for phospho-Rab10 induction will be comparable between G2019S and WT (difference < 20%) | — no observation — | pending | 0.65 |
| IF primary fibroblasts or iPSC-derived neurons carrying G2019S LRRK2 are compared to isogenic wild-type controls, THEN phospho-Rab10 (Ser106) or phospho-Rab8A (Ser72) levels will be significantly elev | Baseline phospho-Rab10/Rab8A levels will be higher in G2019S carriers than in isogenic controls | — no observation — | pending | 0.75 |