G2019S causes elevated baseline RAB10 phosphorylation via chronic ER stress pathway (PERK/eIF2α) unrelated to lysosomal volume-sensing. True signal amplification is pathogenic; baseline elevation is compensatory. PERK inhibitor GSK2606414 can test whether baseline elevation depends on ER stress in both genotypes.
Curated pathway from expert analysis
flowchart TD
A["ER Stress<br/>Unfolded Protein Response"]
B["PERK Activation<br/>Kinase"]
C["eIF2alpha<br/>Phosphorylation"]
D["Integrated Stress<br/>Response (ISR)"]
E["Synaptic Protein<br/>Translation Suppression"]
F["LRRK2 Mutation<br/>G2019S"]
G["Lysosomal<br/>Dysfunction"]
H["Neuronal<br/>Death"]
A --> B
B --> C
C --> D
D --> E
F --> G
G --> H
E --> H
style A fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style H fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9aNo linked papers recorded for this hypothesis yet.
No curated PDB or AlphaFold mapping for PERK yet. Search RCSB →
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 PERK,LRRK2.
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 human iPSC-derived dopaminergic neurons carrying G2019S LRRK2 are treated with 1 μM GSK2606414 (PERK inhibitor) for 24 hours, THEN baseline p-T72 RAB10 will decrease by ≥50% compared to vehicle-tre | Significant reduction in RAB10 phosphorylation at baseline in G2019S neurons following PERK inhibition, with no change in total RAB10 protein levels | — no observation — | pending | 0.75 |
| IF baseline RAB10 phosphorylation is normalized by 72-hour PERK inhibition and neurons are then challenged with 20 μM chloroquine for 2 hours, THEN the relative fold-increase in p-T72 RAB10 will be id | Lysosomal stress-induced RAB10 phosphorylation amplification remains intact after PERK blockade, demonstrating pathway independence from chronic ER stress | — no observation — | pending | 0.65 |