ID: h-434c5d45f5
Hypothesis
Dual-Mechanism Model: G2019S Increases Both Baseline AND Signal-Dependent Phosphorylation (H2)
G2019S has two separable effects: (1) increases catalytic efficiency at baseline (higher floor), AND (2) increases LRRK2 membrane affinity upon lysosomal stress, amplifying volume-sensing signals.
EvidencePending (0%)📖 0 cit🗣 1 debates✓ 3 support✗ 2 oppose
✓ All Quality Gates Passed
🧪 Overview
G2019S has two separable effects: (1) increases catalytic efficiency at baseline (higher floor), AND (2) increases LRRK2 membrane affinity upon lysosomal stress, amplifying volume-sensing signals. These may be pharmacologically separable. Membrane-association mutants could distinguish these mechanisms.
🧬 Mechanism
🧬 Curated Mechanism Pathway
Curated pathway from expert analysis
flowchart TD
A["LRRK2 Mutation<br/>Autosomal Dominant PD"]
B["Kinase Domain<br/>Hyperactivity"]
C["Rab Protein<br/>Phosphorylation Cascade"]
D["Lysosomal<br/>Dysfunction"]
E["Autophagy<br/>Block"]
F["Dopaminergic<br/>Neuron Loss"]
G["Therapeutic Target<br/>Kinase Inhibitors"]
A --> B
B --> C
C --> D
D --> E
E --> F
B --> G
G --> C
style A fill:#6a1b9a,stroke:#ce93d8,color:#ce93d8
style F fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style G fill:#1b5e20,stroke:#a5d6a7,color:#a5d6a7⚖️ Evidence
⚖️ Evidence Matrix3 supports2 contradicts
Contradicts
Activation segment widening affects catalytic function, not membrane affinity
📖 Linked Papers (4)Export BibTeX ↗
Protective or Pathogenic? Kinase activity and the neurodevelopmental origins of G2019S LRRK2-Associated Parkinson's disease.
Parkinsonism & related disorders (2026) · PubMed:41344986 ↗
No figures
Pathological α-synuclein recruits LRRK2 expressing pro-inflammatory monocytes to the brain.
Molecular neurodegeneration (2022) · PubMed:35012605 ↗
No figures
R1441G but not G2019S mutation enhances LRRK2 mediated Rab10 phosphorylation in human peripheral blood neutrophils.
Acta neuropathologica (2022) · PubMed:34125248 ↗
No figures
Interrogating Parkinson's disease LRRK2 kinase pathway activity by assessing Rab10 phosphorylation in human neutrophils.
The Biochemical journal (2018) · PubMed:29127255 ↗
No figures
🏥 Translation
🧬 3D Protein Structure — LRRK2
🧠 GTEx v10 Brain ExpressionJSON
Median TPM across 13 brain regions for LRRK2 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.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
🏆 Tournament
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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 HEK293T cells expressing equivalent levels of GFP-tagged G2019S or wild-type LRRK2 are treated with 10 mM LLOME (leucyl-leucine methyl ester) for 60 minutes to induce lysosomal stress, THEN G2019S- | Membrane fractionation will reveal ≥2-fold enrichment of G2019S LRRK2 in the membrane fraction post-LLOME treatment, with membrane-associated G2019S representin | — no observation — | pending | 0.72 |
| IF primary neurons from G2019S LRRK2 knock-in mice are compared to age-matched wild-type neurons under basal culture conditions (no pharmacological stress), THEN G2019S neurons will exhibit significan | G2019S neurons will show ≥50% higher LRRK2-S1292 autophosphorylation and ≥40% higher Rab10-T72 phosphorylation compared to wild-type controls under baseline con | — no observation — | pending | 0.78 |
🔮 Falsifiable Predictions (2)
pendingconf 78%
IF primary neurons from G2019S LRRK2 knock-in mice are compared to age-matched wild-type neurons under basal culture conditions (no pharmacological stress), THEN G2019S neurons will exhibit significantly higher LRRK2 autophosphorylation at S1292 and increased phosphorylation of the Rab GTPase substr
Predicted outcome: G2019S neurons will show ≥50% higher LRRK2-S1292 autophosphorylation and ≥40% higher Rab10-T72 phosphorylation compared to wild-type controls under ba
Falsification: No significant difference (p>0.05) in LRRK2-S1292 or Rab10-T72 phosphorylation between G2019S and wild-type neurons under baseline conditions, indicating G2019S does not elevate basal catalytic activi
pendingconf 72%
IF HEK293T cells expressing equivalent levels of GFP-tagged G2019S or wild-type LRRK2 are treated with 10 mM LLOME (leucyl-leucine methyl ester) for 60 minutes to induce lysosomal stress, THEN G2019S-expressing cells will show significantly greater membrane-associated LRRK2 fraction (≥2-fold increas
Predicted outcome: Membrane fractionation will reveal ≥2-fold enrichment of G2019S LRRK2 in the membrane fraction post-LLOME treatment, with membrane-associated G2019S r
Falsification: G2019S and wild-type LRRK2 show equivalent membrane association (≤1.2-fold difference) after lysosomal stress, indicating the G2019S mutation does not specifically enhance membrane affinity under stre
▸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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