The strongest biomarker-oriented hypothesis is not that Rab12 is the main pathogenic target, but that pRab12 may outperform pRab10 as a translational readout under chronic lysosomal stress or disease-relevant compartmentalization. This could reflect substrate usage, compartment retention, or reduced phosphatase masking, making paired pRab12:pRab10 measurements more informative than either alone.
Curated pathway from expert analysis
flowchart TD
A["RAB12<br/>Primary Target"]
B["Biological Process 1<br/>Mechanistic Step A"]
C["Biological Process 2<br/>Mechanistic Step B"]
D["Output Phenotype<br/>Disease Effect"]
A --> B
B --> C
C --> D
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style D fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9aNo linked papers recorded for this hypothesis yet.
No curated PDB or AlphaFold mapping for RAB12 yet. Search RCSB →
Median TPM across 13 brain regions for RAB12 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 RAB12.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF we stratify G2019S LRRK2 mutation carriers into manifest (PD-diagnosed) and non-manifest groups, THEN CSF or plasma pRab12 levels will show a larger effect size (Cohen's d > 0.5) for distinguishing | pRab12 will demonstrate superior sensitivity and specificity for identifying phenoconversion or disease severity (MDS-UPDRS III) with AUC > 0.75 versus pRab10 A | — no observation — | pending | 0.65 |
| IF we expose G2019S patient-derived dopaminergic neurons or LRRK2 G2019S knock-in mice to lysosomal stress (chloroquine 20 mg/kg i.p. for 5 days) or LRRK2 kinase inhibition (MLi-2 10 mg/kg for 14 days | pRab12 phosphorylation will change by ≥ 100% from baseline under both conditions, whereas pRab10 will change by < 50%. | — no observation — | pending | 0.55 |