ID: h-a0269f3c81
Hypothesis
G2019S Acts as Lysosomal Volume-Sensing Amplifier via Enhanced RAB29-Dependent Recruitment (H1)
G2019S specifically hyperactivates LRRK2 when recruited to swelling lysosomes via RAB29, creating pathogenic positive feedback where membrane stress increases RAB10 phosphorylation more than wild-type.
EvidencePending (0%)📖 8 cit🗣 1 debates✓ 8 support✗ 2 oppose
✓ All Quality Gates Passed
🧪 Overview
G2019S specifically hyperactivates LRRK2 when recruited to swelling lysosomes via RAB29, creating pathogenic positive feedback where membrane stress increases RAB10 phosphorylation more than wild-type. Key experimental prediction: rise kinetics (slope) should differ between G2019S and WT, not merely baseline offset. RAB29 pathogenic mutations (PARK23) confirm disease relevance of this axis.
🧬 Mechanism
🧬 Curated Mechanism Pathway
Curated pathway from expert analysis
flowchart TD
A["LRRK2 G2019S<br/>Gain of Function"]
B["RAB29 Recruitment<br/>to Lysosomal Membrane"]
C["Enhanced Lysosomal<br/>Volume Sensing"]
D["Signal Amplification<br/>Pathological Threshold"]
E["Lysosomal Dysfunction<br/>Autophagy Impairment"]
F["Neuronal Death<br/>PD Progression"]
G["RAB29 as Modifier<br/>of LRRK2 Pathogenesis"]
A --> B
B --> C
C --> D
D --> E
E --> F
A --> G
G --> C
style A fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style F fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style G fill:#1b5e20,stroke:#a5d6a7,color:#a5d6a7⚖️ Evidence
⚖️ Evidence Matrix8 supports2 contradicts
Supports
Endogenous Rab29 does not impact basal or stimulated LRRK2 pathway activity.
Supports
LRRK2 and Parkinson's disease: from genetics to targeted therapy.
Supports
LRRK2 in Parkinson's disease: upstream regulation and therapeutic targeting.
📖 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.
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▼14.7%💾 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 RAB29 is knocked out via CRISPR-Cas9 in G2019S LRRK2 KI neurons, THEN the amplified RAB10 phosphorylation slope observed under nigericin-induced lysosomal swelling will be abolished, reducing the k | RAB29 knockout eliminates the G2019S-specific enhancement of RAB10 phosphorylation kinetics, resulting in no significant slope difference between G2019S/RAB29-K | — no observation — | pending | 0.72 |
| IF primary cortical neurons from G2019S LRRK2 knock-in mice are treated with nigericin (1 µM) to induce lysosomal swelling, THEN the initial rate (slope, 0-30 min) of RAB10 phosphorylation at Thr72 wi | G2019S neurons show a significantly steeper rise in RAB10-pThr72 signal over the first 30 minutes of lysosomal swelling compared to WT neurons, with the slope d | — no observation — | pending | 0.78 |
🔮 Falsifiable Predictions (2)
pendingconf 78%
IF primary cortical neurons from G2019S LRRK2 knock-in mice are treated with nigericin (1 µM) to induce lysosomal swelling, THEN the initial rate (slope, 0-30 min) of RAB10 phosphorylation at Thr72 will increase significantly more (>50% steeper) compared to WT neurons, as measured by quantitative ph
Predicted outcome: G2019S neurons show a significantly steeper rise in RAB10-pThr72 signal over the first 30 minutes of lysosomal swelling compared to WT neurons, with t
Falsification: If the kinetic slope (rate of RAB10 phosphorylation increase) is not significantly different between G2019S and WT neurons (95% CI overlap) OR if only baseline/offset differences exist without slope d
pendingconf 72%
IF RAB29 is knocked out via CRISPR-Cas9 in G2019S LRRK2 KI neurons, THEN the amplified RAB10 phosphorylation slope observed under nigericin-induced lysosomal swelling will be abolished, reducing the kinetic difference to <15% compared to WT+RAB29-KO neurons.
Predicted outcome: RAB29 knockout eliminates the G2019S-specific enhancement of RAB10 phosphorylation kinetics, resulting in no significant slope difference between G201
Falsification: If G2019S/RAB29-KO neurons retain significantly steeper RAB10 phosphorylation slopes (>30% difference) compared to WT/RAB29-KO under lysosomal swelling, the RAB29-dependence of the amplification mecha
▸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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