RAB29 functions as a gatekeeper—when lysosomes swell, RAB29-GTP increases, recruits LRRK2, and G2019S hyperphosphorylates RAB10 disproportionately. The amplification is RAB29-dependent. Strategic pivot: RAB29 serves as predictive biomarker rather than drug target. RAB29 knockout in G2019S patient-derived neurons would determine if amplification requires RAB29.
Curated pathway from expert analysis
flowchart TD
A["RAB29 GTPase<br/>Activity"]
B["Recruitment to<br/>Stressed Lysosomes"]
C["Enhanced LRRK2-mediated<br/>Rab Phosphorylation"]
D["Lysosomal<br/>Dysfunction"]
E["Autophagy<br/>Impairment"]
F["Neuronal<br/>Death"]
G["Modifier of LRRK2<br/>Pathogenesis"]
A --> B
B --> C
C --> D
D --> E
E --> F
A --> G
G --> C
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style F fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style G fill:#1b5e20,stroke:#a5d6a7,color:#a5d6a7No linked papers recorded for this hypothesis yet.
No curated PDB or AlphaFold mapping for RAB29 yet. Search RCSB →
Median TPM across 13 brain regions for 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 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 CRISPR-Cas9-mediated RAB29 knockout is performed in G2019S patient-derived iPSC neurons, THEN RAB10 phosphorylation at Thr73 will be reduced by at least 50% compared to isogenic G2019S control neur | At least 50% reduction in phospho-RAB10 (Thr73) levels in RAB29 knockout G2019S neurons relative to G2019S parental neurons, as measured by multiplex immunoassa | — no observation — | pending | 0.72 |
| IF RAB29 is overexpressed via AAV-mediated transduction in non-swollen lysosomes of G2019S patient-derived neurons, THEN LRRK2-mediated RAB10 phosphorylation will not increase above baseline, whereas | AAV-RAB29 overexpression alone will not elevate phospho-RAB10; however, pretreatment with hypotonic medium (5-10 min) to induce lysosome swelling will produce s | — no observation — | pending | 0.68 |