G2019S specifically hyperactivates LRRK2 when recruited to swelling lysosomes via RAB29, creating pathogenic positive feedback where membrane stress increases RAB10 phosphorylation more than wild-type. Key experimental prediction: rise kinetics (slope) should differ between G2019S and WT, not merely baseline offset. RAB29 pathogenic mutations (PARK23) confirm disease relevance of this axis.
Curated pathway from expert analysis
flowchart TD
A["LRRK2 G2019S<br/>Gain of Function"]
B["RAB29 Recruitment<br/>to Lysosomal Membrane"]
C["Enhanced Lysosomal<br/>Volume Sensing"]
D["Signal Amplification<br/>Pathological Threshold"]
E["Lysosomal Dysfunction<br/>Autophagy Impairment"]
F["Neuronal Death<br/>PD Progression"]
G["RAB29 as Modifier<br/>of LRRK2 Pathogenesis"]
A --> B
B --> C
C --> D
D --> E
E --> F
A --> G
G --> C
style A fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style F fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style G fill:#1b5e20,stroke:#a5d6a7,color:#a5d6a7No 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 RAB29 is knocked out via CRISPR-Cas9 in G2019S LRRK2 KI neurons, THEN the amplified RAB10 phosphorylation slope observed under nigericin-induced lysosomal swelling will be abolished, reducing the k | RAB29 knockout eliminates the G2019S-specific enhancement of RAB10 phosphorylation kinetics, resulting in no significant slope difference between G2019S/RAB29-K | — no observation — | pending | 0.72 |
| IF primary cortical neurons from G2019S LRRK2 knock-in mice are treated with nigericin (1 µM) to induce lysosomal swelling, THEN the initial rate (slope, 0-30 min) of RAB10 phosphorylation at Thr72 wi | G2019S neurons show a significantly steeper rise in RAB10-pThr72 signal over the first 30 minutes of lysosomal swelling compared to WT neurons, with the slope d | — no observation — | pending | 0.78 |