ID: h-36d21444fd
Hypothesis
G2019S Amplifies Lysosomal Volume-Sensing Through Membrane Microdomain Partitioning (H5)
G2019S increases LRRK2 affinity for negatively charged, curved membranes (PI4P-enriched lysosomal membranes during swelling).
EvidencePending (0%)📖 0 cit🗣 1 debates✓ 3 support✗ 2 oppose
✓ All Quality Gates Passed
🧪 Overview
G2019S increases LRRK2 affinity for negatively charged, curved membranes (PI4P-enriched lysosomal membranes during swelling). This is not a kinase catalytic change but a localization change that amplifies local RAB10 phosphorylation. dSTORM microscopy can quantify membrane density differences between G2019S and WT.
🧬 Mechanism
🧬 Curated Mechanism Pathway
Curated pathway from expert analysis
flowchart TD
A["LRRK2 Mutation<br/>Kinase Hyperactivity"]
B["PI4P Phosphorylation<br/>Lipid Kinase Substrate"]
C["Lysosomal Membrane<br/>Lipid Composition"]
D["Endomembrane<br/>Trafficking Defect"]
E["Autophagy-Lysosome<br/>Pathway Impairment"]
F["Neuronal<br/>Degeneration"]
A --> B
B --> C
C --> D
D --> E
E --> F
style A fill:#6a1b9a,stroke:#ce93d8,color:#ce93d8
style F fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a⚖️ Evidence
⚖️ Evidence Matrix3 supports2 contradicts
Supports
G2019S accelerates LRRK2 autophosphorylation on S1292 (membrane-associated site)
Contradicts
G2019S is in kinase domain—structural mechanism for membrane affinity change unexplained
Contradicts
S1292 evidence is indirect marker of membrane association, not direct mechanism
📖 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,PI4P 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,PI4P.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
🏆 Tournament
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📊 Market Indicators
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▼5.1%💾 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 knock-in mouse embryonic fibroblasts (MEFs) are treated with VPS34 inhibitor (SAR405, 100nM, 2h) to reduce PI4P synthesis, THEN the amplitude of lysosomal volume-dependent RAB10 phosphorylat | VPS34 inhibition will preferentially attenuate volume-sensing-induced RAB10 phosphorylation in G2019S cells, demonstrating that G2019S amplification depends on | — no observation — | pending | 0.58 |
| IF primary human fibroblasts harboring G2019S LRRK2 are subjected to hyperosmotic stress (200mM sucrose, 30 min) to induce lysosomal swelling, THEN phospho-RAB10 (T73) levels at isolated lysosomal mem | Lysosome-associated phospho-RAB10 (T73) will be significantly elevated (>50%) in G2019S cells vs. WT controls after osmotic stress, with LRRK2 showing increased | — no observation — | pending | 0.65 |
🔮 Falsifiable Predictions (2)
pendingconf 65%
IF primary human fibroblasts harboring G2019S LRRK2 are subjected to hyperosmotic stress (200mM sucrose, 30 min) to induce lysosomal swelling, THEN phospho-RAB10 (T73) levels at isolated lysosomal membranes will increase by >50% compared to age-matched WT fibroblasts, within 60 minutes of stress ons
Predicted outcome: Lysosome-associated phospho-RAB10 (T73) will be significantly elevated (>50%) in G2019S cells vs. WT controls after osmotic stress, with LRRK2 showing
Falsification: Phospho-RAB10 levels at lysosomal fractions do not differ between G2019S and WT fibroblasts after osmotic challenge (difference <20%), or LRRK2 shows equal membrane partitioning regardless of genotype
pendingconf 58%
IF G2019S knock-in mouse embryonic fibroblasts (MEFs) are treated with VPS34 inhibitor (SAR405, 100nM, 2h) to reduce PI4P synthesis, THEN the amplitude of lysosomal volume-dependent RAB10 phosphorylation will be reduced to <30% of vehicle-treated G2019S MEFs, whereas VPS34 inhibition in WT MEFs will
Predicted outcome: VPS34 inhibition will preferentially attenuate volume-sensing-induced RAB10 phosphorylation in G2019S cells, demonstrating that G2019S amplification d
Falsification: VPS34 inhibition reduces RAB10 phosphorylation equally in G2019S and WT MEFs (>70% reduction in both), indicating G2019S does not specifically amplify PI4P-dependent lysosomal volume-sensing.
▸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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