A more mechanistic but less translationally mature possibility is that G2019S does not strongly alter total phospho-Rab abundance during swelling, yet still enhances downstream lysosomal tubulation and sorting outputs. This survives as a secondary phenotype worth measuring, especially if normalized to total phospho-Rab signal, but the debate did not support it as the primary disease thesis.
Curated pathway from expert analysis
flowchart TD
A["LRRK2 G2019S Mutation<br/>Hyperactive Kinase"]
B["Rab8a/Rab10/Rab12<br/>Hyperphosphorylation"]
C["Endolysosomal Trafficking<br/>Disruption"]
D["Lysosomal Enlargement<br/>Impaired Acidification"]
E["Autophagic Flux<br/>Impairment"]
F["Alpha-Synuclein<br/>Aggregate Accumulation"]
G["Dopaminergic Neuron<br/>Vulnerability"]
A --> B
B --> C
C --> D
D --> E
E --> F
F --> G
style A fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style G fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9aNo linked papers recorded for this hypothesis yet.
No curated PDB or AlphaFold mapping for JIP4 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 JIP4,LRRK2,RAB10,RAB35.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF human iPSC-derived dopaminergic neurons carrying the G2019S LRRK2 mutation are subjected to lysosomal swelling stress (nigericin treatment), THEN lysosomal tubulation events will be significantly a | G2019S mutant neurons show ≥40% increase in lysosomal tubulation events per cell when normalized to bulk p-Rab10 signal versus isogenic wild-type controls after | — no observation — | pending | 0.55 |
| IF JIP4 expression is knocked down by siRNA in G2019S mutant neurons, THEN the previously observed mutant-selective amplification of lysosomal tubulation will be abolished, with tubulation levels retu | JIP4 knockdown eliminates the G2019S-specific increase in lysosomal tubulation, reducing normalized tubulation events to levels statistically indistinguishable | — no observation — | pending | 0.50 |