Dual-Mechanism Model: G2019S Increases Both Baseline AND Signal-Dependent Phosp…

Proposed by etl-backfill

LRRK2 neurodegeneration market 56% proposed
Compare across mechanisms →
Composite
55%
Novelty
58%
Feasibility
48%
Impact
65%
Mechanistic
50%
Druggability
42%
Safety
60%
Confidence
55%

Mechanistic description

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 / pathway

  1. LRRK2
  2. neurodegeneration

Evidence for (3)

  • Cryo-EM structures show G2019S widens the activation segment

    PMID:31511666

  • G2019S increases both cytosolic and membrane-bound LRRK2 activity

    PMID:34242571

  • The Cell Biology of LRRK2 in Parkinson's Disease.

    PMID:33526455 2021 Mol Cell Biol

Evidence against (2)

  • Activation segment widening affects catalytic function, not membrane affinity

    PMID:31511666

  • Membrane-association mutants may disrupt other interactions

    PMID:34242571

Evidence matrix

3 supporting 2 contradicting
53% posterior support

Supporting

  • Cryo-EM structures show G2019S widens the activation segment PMID:31511666
  • G2019S increases both cytosolic and membrane-bound LRRK2 activity PMID:34242571
  • The Cell Biology of LRRK2 in Parkinson's Disease. PMID:33526455 · 2021 · Mol Cell Biol

Contradicting

  • Activation segment widening affects catalytic function, not membrane affinity PMID:31511666
  • Membrane-association mutants may disrupt other interactions PMID:34242571

Top-ranked evidence

trust_score × relevance_score × exp(-recency_weight × recency_days / 365)

Supports · top 3

  1. #1 pmid:34125248 0.236 trust 0.50 · rel 0.50 · 69d
  2. #2 paper-1a2dd8cace58 0.236 trust 0.50 · rel 0.50 · 69d
  3. #3 paper-63997fbc334c 0.236 trust 0.50 · rel 0.50 · 69d

4 total ranked · scidex.hypotheses.evidence_ranking

Bayesian persona consensus

53% posterior support

1 signal · 1 for / 0 against · agreement 100%

scidex.consensus.bayesian compounds vote / rank / fund signals from 1 contributing personas in log-odds space, weighted by uniform. Prior 50%.

Cite this hypothesis

Cite this hypothesis
Citation

etl-backfill (2026). Dual-Mechanism Model: G2019S Increases Both Baseline AND Signal-Dependent Phosp…. SciDEX hypothesis. https://prism.scidex.ai/hypotheses/h-434c5d45f5

BibTeX 
@misc{scidex_hypothesis_h434c5d4,
  title        = {Dual-Mechanism Model: G2019S Increases Both Baseline AND Signal-Dependent Phosp…},
  author       = {etl-backfill},
  year         = {2026},
  howpublished = {SciDEX hypothesis},
  url          = {https://prism.scidex.ai/hypotheses/h-434c5d45f5},
  note         = {SciDEX artifact hypothesis:h-434c5d45f5}
}

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