G2019S increases LRRK2 affinity for negatively charged, curved membranes (PI4P-enriched lysosomal membranes during swelling). This is not a kinase catalytic change but a localization change that amplifies local RAB10 phosphorylation. dSTORM microscopy can quantify membrane density differences between G2019S and WT.
Curated pathway from expert analysis
flowchart TD
A["LRRK2 Mutation<br/>Kinase Hyperactivity"]
B["PI4P Phosphorylation<br/>Lipid Kinase Substrate"]
C["Lysosomal Membrane<br/>Lipid Composition"]
D["Endomembrane<br/>Trafficking Defect"]
E["Autophagy-Lysosome<br/>Pathway Impairment"]
F["Neuronal<br/>Degeneration"]
A --> B
B --> C
C --> D
D --> E
E --> F
style A fill:#6a1b9a,stroke:#ce93d8,color:#ce93d8
style F fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9aNo linked papers recorded for this hypothesis yet.
Median TPM across 13 brain regions for LRRK2,PI4P 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,PI4P.
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 G2019S knock-in mouse embryonic fibroblasts (MEFs) are treated with VPS34 inhibitor (SAR405, 100nM, 2h) to reduce PI4P synthesis, THEN the amplitude of lysosomal volume-dependent RAB10 phosphorylat | VPS34 inhibition will preferentially attenuate volume-sensing-induced RAB10 phosphorylation in G2019S cells, demonstrating that G2019S amplification depends on | — no observation — | pending | 0.58 |
| IF primary human fibroblasts harboring G2019S LRRK2 are subjected to hyperosmotic stress (200mM sucrose, 30 min) to induce lysosomal swelling, THEN phospho-RAB10 (T73) levels at isolated lysosomal mem | Lysosome-associated phospho-RAB10 (T73) will be significantly elevated (>50%) in G2019S cells vs. WT controls after osmotic stress, with LRRK2 showing increased | — no observation — | pending | 0.65 |