Even if G2019S mainly elevates the kinase floor, that increase may still become pathogenic by pushing a thresholded downstream program in which swollen lysosomes recruit LRRK2, phosphorylate Rab10, engage JIP4-dependent remodeling, and increase extracellular alpha-synuclein release. This is plausible disease biology and a useful secondary discriminator, but it remains less direct than the baseline-versus-gain question.
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,JIP4,SNCA 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,JIP4,SNCA.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF JIP4 is knocked down (siRNA, 72h) in differentiated SH-SY5Y cells co-expressing G2019S LRRK2 and wild-type alpha-synuclein under thapsigargin-induced lysosomal stress, THEN extracellular alpha-synu | ≥40% reduction in extracellular alpha-synuclein (ELISA) and ≥60% knockdown of JIP4 protein (western blot) | — no observation — | pending | 0.55 |
| IF primary neurons from G2019S LRRK2 knock-in mice are treated with a selective LRRK2 kinase inhibitor (MLi-2, 100 nM) for 48 hours under nigericin-induced lysosomal stress, THEN extracellular alpha-s | ≥50% reduction in extracellular alpha-synuclein monomer concentration (measured by ELISA) in conditioned media | — no observation — | pending | 0.65 |