From Analysis:
The debate highlighted that G2019S shows elevated baseline RAB10 phosphorylation, but it's unclear whether this represents true signal amplification during lysosomal swelling or just a higher activity floor. This distinction is crucial for understanding disease mechanisms and therapeutic targeting. Source: Debate session sess_SDA-2026-04-16-gap-pubmed-20260410-170027-a1e5f867_20260416-135352 (Analysis: SDA-2026-04-16-gap-pubmed-20260410-170027-a1e5f867)
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.
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Curated pathway diagram from expert analysis
flowchart TD
A["LRRK2 Mutation
Autosomal Dominant PD"]
B["Kinase Domain
Hyperactivity"]
C["Rab Protein
Phosphorylation Cascade"]
D["Lysosomal
Dysfunction"]
E["Autophagy
Block"]
F["Dopaminergic
Neuron Loss"]
G["Therapeutic Target
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
Median TPM across 13 brain regions for LRRK2 from GTEx v10.
Mechanism: G2019S specifically hyperactivates LRRK2 when recruited to swelling lysosomes via RAB29, creating a pathogenic positive feedback loop where membrane stress increases RAB10 phosphorylation more than wild-type.
Target Gene/Protein: LRRK2 (G2019S) + RAB29 axis
Supporting Evidence:
The core question—whether G2019S increases signal amplification during lysosomal swelling versus merely elevating the baseline activity floor—requires distinguishing between these mechanistically distinct possibilities. Most hypotheses conflate these, and none provide decisive evidence for either model.
The core mechanistic question—whether LRRK2 G2019S drives pathology through amplified signaling during lysosomal stress versus simply elevating the basal activity floor—carries significant therapeutic implications. If amplification is pathogenic, partial kinase inhibition strategies become rational; if elevated baseline alone drives neurodegeneration, complete inhibition may be required. This distinction will shape trial design, dose selection, and acceptable safety profiles.
B
No clinical trials data available
Freshness score = exp(-age×ln2/5): halves every 5 years. Green >0.6, Amber 0.3–0.6, Red <0.3.
No citation freshness data yet. Export bibliography — run scripts/audit_citation_freshness.py to populate.
Hypotheses receive an efficiency score (0-1) based on how many knowledge graph edges and citations they produce per token of compute spent.
High-efficiency hypotheses (score >= 0.8) get a price premium in the market, pulling their price toward $0.580.
Low-efficiency hypotheses (score < 0.6) receive a discount, pulling their price toward $0.420.
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Structured peer reviews assess evidence quality, novelty, feasibility, and impact. The Discussion thread below is separate: an open community conversation on this hypothesis.
No DepMap CRISPR Chronos data found for LRRK2.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
No curated ClinVar variants loaded for this hypothesis.
Run scripts/backfill_clinvar_variants.py to fetch P/LP/VUS variants.
No governance decisions recorded for this hypothesis.
Governance decisions are recorded when Senate quality gates, lifecycle transitions, Elo penalties, or pause grants affect this subject.
Molecular pathway showing key causal relationships underlying this hypothesis
graph TD
LRRK2_knockout["LRRK2 knockout"] -->|preserves| mouse_viability["mouse viability"]
LRRK2_G2019S["LRRK2 G2019S"] -->|causes| RAB10_hyperphosphorylatio["RAB10 hyperphosphorylation"]
LRRK2_G2019S_1["LRRK2 G2019S"] -->|amplifies| lysosomal_stress_response["lysosomal stress response"]
LRRK2_G2019S_2["LRRK2 G2019S"] -->|enhances| RAB10_phosphorylation["RAB10 phosphorylation"]
lysosomal_swelling["lysosomal swelling"] -->|induces| LRRK2_activation["LRRK2 activation"]
RAB29_GTP["RAB29-GTP"] -->|regulates| lysosomal_recruitment_of_["lysosomal recruitment of LRRK2"]
LRRK2_kinase_inhibitors["LRRK2 kinase inhibitors"] -->|prevents| neurodegeneration_models["neurodegeneration models"]
partial_LRRK2_inhibition["partial LRRK2 inhibition"] -->|normalizes| stress_induced_RAB10_phos["stress-induced RAB10 phosphorylation spikes"]
stress["stress"] -->|triggers| LRRK2_G2019S_pathogenic_s["LRRK2 G2019S pathogenic signaling"]
RAB29["RAB29"] -->|regulates| LRRK2_activation_at_lysos["LRRK2 activation at lysosomes"]
RAB29_3["RAB29"] -->|modulates| LRRK2_G2019S_pathogenic_s_4["LRRK2 G2019S pathogenic signaling"]
LRRK2_G2019S_5["LRRK2 G2019S"] -->|causes| endosomal_trafficking_def["endosomal trafficking defects"]
RAB29_knockout["RAB29 knockout"] -->|prevents| LRRK2_G2019S_phenotypes["LRRK2 G2019S phenotypes"]
LRRK2_kinase_inhibitors_6["LRRK2 kinase inhibitors"] -->|prevents| G2019S_neurodegeneration_["G2019S neurodegeneration models"]
stress_response_signaling["stress-response signaling"] -->|drives| LRRK2_G2019S_pathogenesis["LRRK2 G2019S pathogenesis"]
style LRRK2_knockout fill:#4fc3f7,stroke:#333,color:#000
style mouse_viability fill:#4fc3f7,stroke:#333,color:#000
style LRRK2_G2019S fill:#ce93d8,stroke:#333,color:#000
style RAB10_hyperphosphorylatio fill:#4fc3f7,stroke:#333,color:#000
style LRRK2_G2019S_1 fill:#4fc3f7,stroke:#333,color:#000
style lysosomal_stress_response fill:#4fc3f7,stroke:#333,color:#000
style LRRK2_G2019S_2 fill:#4fc3f7,stroke:#333,color:#000
style RAB10_phosphorylation fill:#4fc3f7,stroke:#333,color:#000
style lysosomal_swelling fill:#4fc3f7,stroke:#333,color:#000
style LRRK2_activation fill:#4fc3f7,stroke:#333,color:#000
style RAB29_GTP fill:#4fc3f7,stroke:#333,color:#000
style lysosomal_recruitment_of_ fill:#4fc3f7,stroke:#333,color:#000
style LRRK2_kinase_inhibitors fill:#4fc3f7,stroke:#333,color:#000
style neurodegeneration_models fill:#4fc3f7,stroke:#333,color:#000
style partial_LRRK2_inhibition fill:#4fc3f7,stroke:#333,color:#000
style stress_induced_RAB10_phos fill:#4fc3f7,stroke:#333,color:#000
style stress fill:#4fc3f7,stroke:#333,color:#000
style LRRK2_G2019S_pathogenic_s fill:#4fc3f7,stroke:#333,color:#000
style RAB29 fill:#4fc3f7,stroke:#333,color:#000
style LRRK2_activation_at_lysos fill:#4fc3f7,stroke:#333,color:#000
style RAB29_3 fill:#4fc3f7,stroke:#333,color:#000
style LRRK2_G2019S_pathogenic_s_4 fill:#4fc3f7,stroke:#333,color:#000
style LRRK2_G2019S_5 fill:#ce93d8,stroke:#333,color:#000
style endosomal_trafficking_def fill:#4fc3f7,stroke:#333,color:#000
style RAB29_knockout fill:#ce93d8,stroke:#333,color:#000
style LRRK2_G2019S_phenotypes fill:#4fc3f7,stroke:#333,color:#000
style LRRK2_kinase_inhibitors_6 fill:#4fc3f7,stroke:#333,color:#000
style G2019S_neurodegeneration_ fill:#4fc3f7,stroke:#333,color:#000
style stress_response_signaling fill:#81c784,stroke:#333,color:#000
style LRRK2_G2019S_pathogenesis fill:#4fc3f7,stroke:#333,color:#000
neurodegeneration | 2026-04-23 | abandoned
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