A credible refinement is that any true amplification is not universal across cell types, but emerges most strongly in professional phagocytes with high endogenous LRRK2 activity, chronic cargo load, and active endolysosomal remodeling. This would reconcile modest blood-cell baseline effects with larger functional consequences in microglia/macrophages relevant to inflammatory and trafficking phenotypes.
Curated pathway from expert analysis
flowchart TD
A["LRRK2 G2019S Mutation<br/>Kinase Hyperactivity"]
B["RAB10 Activation<br/>GTP-bound State"]
C["RAB10 Phosphorylation<br/>T73 on ExoCycling Machinery"]
D["GLUT4 Translocation<br/>Endosomal Recycling Defect"]
E["ER-to-Golgi Transport<br/>Vesicle Cargo Delay"]
F["Synaptic Vesicle Pool<br/>Reduced Recycling Rate"]
G["Neuronal Homeostasis<br/>Impaired Lysosomal Trafficking"]
H["alpha-Synuclein Aggregation<br/>PD-Relevant Pathology"]
A --> B
B --> C
C --> D
D --> E
E --> F
F --> G
C --> G
G --> H
style A fill:#7b1fa2,stroke:#ce93d8,color:#ce93d8
style H fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9aNo linked papers recorded for this hypothesis yet.
Median TPM across 13 brain regions for LRRK2,RAB10 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,RAB10.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF LRRK2 G2019S primary microglia and CD14+ peripheral monocytes are treated with LRRK2 kinase inhibitor MLi-2 (100 nM) for 24 hours, THEN pT73 RAB10 phosphorylation will be suppressed by >50% in micr | Microglia will show significantly greater RAB10 phosphorylation suppression than monocytes following LRRK2 inhibition, confirming cell-type-specific amplificati | — no observation — | pending | 0.45 |
| IF LRRK2 G2019S microglia are stimulated with aggregated α-synuclein (1 µg/mL) for 48 hours, THEN RAB10-GTP loading will increase >2-fold relative to vehicle control, while peritoneal macrophages from | Microglia will demonstrate stronger RAB10 activation than peritoneal macrophages in response to neurodegeneration-relevant cargo load, confirming professional p | — no observation — | pending | 0.42 |