Normally RAB29 recruits LRRK2 specifically to stressed lysosomes for localized RAB10 phosphorylation. G2019S increases kinase activity even in cytosolic/untargeted LRRK2, creating diffuse RAB10 phosphorylation that disrupts normal endosomal trafficking. RAB29 overexpression rescuing G2019S phenotypes suggests spatial control not completely uncoupled.
Curated pathway from expert analysis
flowchart TD
A["LRRK2 Mutation<br/>G2019S Kinase Hyperactivity"]
B["RAB29 Recruitment<br/>Lysosomal Membrane"]
C["Enhanced Lysosomal<br/>Volume Sensing"]
D["Signal Amplification<br/>Pathological Threshold"]
E["Lysosomal<br/>Dysfunction"]
F["Autophagy<br/>Impairment"]
G["Neuronal Death<br/>PD Progression"]
A --> B
B --> C
C --> D
D --> E
E --> F
F --> G
style A fill:#6a1b9a,stroke:#ce93d8,color:#ce93d8
style G fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9aNo linked papers recorded for this hypothesis yet.
Median TPM across 13 brain regions for LRRK2,RAB29 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,RAB29.
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-associated phenotypes arise from cytosolic LRRK2 kinase activity uncoupled from RAB29-dependent recruitment, THEN selective pharmacological inhibition of LRRK2 (MLi-2, 100nM, 4h) will reduce | RAB10-pT73 levels will decrease significantly (p<0.001, ANOVA with Tukey's) and distribution will shift from cytosolic to lysosome-associated puncta, matching w | — no observation — | pending | 0.72 |
| IF LRRK2 G2019S neurons are transduced with RAB29 overexpression vector, THEN the rescued phenotype will include restoration of RAB10 phosphorylation to lysosome-proximal puncta (≥80% colocalization w | RAB10-pT73 signal will show punctate lysosomal enrichment rather than diffuse cytosolic distribution, with retrograde transport of fluorescently-labeled BDNF or | — no observation — | pending | 0.75 |