ID: h-377232dcc8
Hypothesis
LRRK2 G2019S Uncouples RAB29-Dependent Spatial Control from Kinase Activity (H7)
Normally RAB29 recruits LRRK2 specifically to stressed lysosomes for localized RAB10 phosphorylation.
EvidencePending (0%)📖 0 cit🗣 1 debates✓ 3 support✗ 2 oppose
✓ All Quality Gates Passed
🧪 Overview
Normally RAB29 recruits LRRK2 specifically to stressed lysosomes for localized RAB10 phosphorylation. G2019S increases kinase activity even in cytosolic/untargeted LRRK2, creating diffuse RAB10 phosphorylation that disrupts normal endosomal trafficking. RAB29 overexpression rescuing G2019S phenotypes suggests spatial control not completely uncoupled.
🧬 Mechanism
🧬 Curated Mechanism Pathway
Curated pathway from expert analysis
flowchart TD
A["LRRK2 Mutation<br/>G2019S Kinase Hyperactivity"]
B["RAB29 Recruitment<br/>Lysosomal Membrane"]
C["Enhanced Lysosomal<br/>Volume Sensing"]
D["Signal Amplification<br/>Pathological Threshold"]
E["Lysosomal<br/>Dysfunction"]
F["Autophagy<br/>Impairment"]
G["Neuronal Death<br/>PD Progression"]
A --> B
B --> C
C --> D
D --> E
E --> F
F --> G
style A fill:#6a1b9a,stroke:#ce93d8,color:#ce93d8
style G fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a⚖️ Evidence
⚖️ Evidence Matrix3 supports2 contradicts
Supports
Combined Knockout of Lrrk2 and Rab29 Does Not Result in Behavioral Abnormalities in vivo.
📖 Linked Papers
No linked papers recorded for this hypothesis yet.
🏥 Translation
🧬 3D Protein Structure — LRRK2
🧠 GTEx v10 Brain ExpressionJSON
Median TPM across 13 brain regions for LRRK2,RAB29 from GTEx v10.
💉 Clinical Trials
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,RAB29.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
🏆 Tournament
🏆 Arenas / Elo
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📊 Market Indicators
7d Trend
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Stable
7d Momentum
▼ 0.6%
Volatility
Low
0.0032
Events (7d)
2
Price History
▼10.5%💾 Resource Usage
No resource usage or linked notebooks recorded for this hypothesis yet.
🔮 Predictions
🔎 Predictions vs Observations2 predictions · 0 with recorded observations
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF G2019S-associated phenotypes arise from cytosolic LRRK2 kinase activity uncoupled from RAB29-dependent recruitment, THEN selective pharmacological inhibition of LRRK2 (MLi-2, 100nM, 4h) will reduce | RAB10-pT73 levels will decrease significantly (p<0.001, ANOVA with Tukey's) and distribution will shift from cytosolic to lysosome-associated puncta, matching w | — no observation — | pending | 0.72 |
| IF LRRK2 G2019S neurons are transduced with RAB29 overexpression vector, THEN the rescued phenotype will include restoration of RAB10 phosphorylation to lysosome-proximal puncta (≥80% colocalization w | RAB10-pT73 signal will show punctate lysosomal enrichment rather than diffuse cytosolic distribution, with retrograde transport of fluorescently-labeled BDNF or | — no observation — | pending | 0.75 |
🔮 Falsifiable Predictions (2)
pendingconf 75%
IF LRRK2 G2019S neurons are transduced with RAB29 overexpression vector, THEN the rescued phenotype will include restoration of RAB10 phosphorylation to lysosome-proximal puncta (≥80% colocalization with LAMP2) and normalization of endocytic cargo trafficking rates to wild-type levels within 7 days
Predicted outcome: RAB10-pT73 signal will show punctate lysosomal enrichment rather than diffuse cytosolic distribution, with retrograde transport of fluorescently-label
Falsification: If RAB29 overexpression fails to re-establish lysosomal RAB10 phosphorylation localization (remains >50% diffuse) OR endosomal trafficking defects persist unchanged, the hypothesis that spatial contro
pendingconf 72%
IF G2019S-associated phenotypes arise from cytosolic LRRK2 kinase activity uncoupled from RAB29-dependent recruitment, THEN selective pharmacological inhibition of LRRK2 (MLi-2, 100nM, 4h) will reduce total cellular RAB10-pT73 by ≥70% and restore lysosomal RAB10 localization without requiring RAB29
Predicted outcome: RAB10-pT73 levels will decrease significantly (p<0.001, ANOVA with Tukey's) and distribution will shift from cytosolic to lysosome-associated puncta,
Falsification: If MLi-2 treatment reduces total RAB10 phosphorylation but RAB10 remains diffusely distributed (cytosolic/cytoplasmic >50% of signal), the spatial uncoupling model is falsified, indicating kinase acti
▸Metadatasource: v1_phase_c_backfill · origin_type: debate_synthesizer
| source | v1_phase_c_backfill |
| origin_type | debate_synthesizer |
| _schema_version | 1 |
📊 Evidence Profile
Evidence Balance
+0%
Certainty
0%
Debates
0
Incoming
0
Outgoing
0
0 supporting
0 contradicting
0 neutral
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