LRRK2 G2019S gain-of-function mutation hyperactivates kinase activity, dysregulating RAB GTPases and impairing lysosomal function, permitting α-synuclein oligomer accumulation. LRRK2 inhibitors (BIIB122, DNL151) restore lysosomal acidification and clearance. Major barriers include NHP lung toxicity findings requiring reformulation, incomplete penetrance of G2019S in humans, and minimal spontaneous α-synuclein pathology in G2019S knock-in mice without additional stressors.
Curated pathway from expert analysis
flowchart TD
A["LRRK2 G2019S<br/>Gain of Function"]
B["Increased Kinase<br/>Activity"]
C["Rab29 Recruitment<br/>Lysosomal Membrane"]
D["Enhanced Lysosomal<br/>Volume Sensing"]
E["Lysosomal<br/>Dysfunction"]
F["Autophagy<br/>Impairment"]
G["Neuronal<br/>Cell Death"]
H["Therapeutic Window<br/>Kinase Inhibitors"]
A --> B
B --> C
C --> D
D --> E
E --> F
F --> G
B --> H
style A fill:#6a1b9a,stroke:#ce93d8,color:#ce93d8
style G fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style H fill:#1b5e20,stroke:#a5d6a7,color:#a5d6a7No linked papers recorded for this hypothesis yet.
Median TPM across 13 brain regions for LRRK2 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.
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 C57BL/6J mice receiving stereotactic injection of pre-formed α-synuclein fibrils (PFFs) into the striatum are treated with DNL151 (50 mg/kg/day oral gavage) for 12 weeks, THEN we will observe a ≥35 | Reduced α-synuclein pathology spread (35-50% decrease in pS129 α-synuclein) and decreased inclusion formation in anatomically connected brain regions | — no observation — | pending | 0.70 |
| IF human iPSC-derived neurons harboring LRRK2 G2019S are treated with BIIB122 (100 nM) for 72 hours, THEN we will observe a ≥40% increase in lysosomal acidification (measured by LysoSensor Green DND-1 | Increased lysosomal acidification (pH decrease of ≥0.5 units) and reduced α-synuclein oligomer accumulation by 30-50% | — no observation — | pending | 0.75 |