G2019S Amplifies Lysosomal Volume-Sensing Through Membrane Microdomain Partitio…

Proposed by etl-backfill

LRRK2,PI4P neurodegeneration market 57% proposed
Compare across mechanisms →
Composite
56%
Novelty
68%
Feasibility
70%
Impact
52%
Mechanistic
40%
Druggability
48%
Safety
58%
Confidence
45%

Mechanistic description

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 / pathway

  1. LRRK2,PI4P
  2. neurodegeneration

Evidence for (3)

  • LRRK2 membrane localization requires PI4P

    PMID:35189339

  • Lysosomal swelling increases PI4P on limiting membrane

    PMID:34242571

  • G2019S accelerates LRRK2 autophosphorylation on S1292 (membrane-associated site)

    PMID:25485852

Evidence against (2)

  • G2019S is in kinase domain—structural mechanism for membrane affinity change unexplained

    PMID:31511666

  • S1292 evidence is indirect marker of membrane association, not direct mechanism

    PMID:25485852

Evidence matrix

3 supporting 2 contradicting
53% posterior support

Supporting

  • LRRK2 membrane localization requires PI4P PMID:35189339
  • Lysosomal swelling increases PI4P on limiting membrane PMID:34242571
  • G2019S accelerates LRRK2 autophosphorylation on S1292 (membrane-associated site) PMID:25485852

Contradicting

  • G2019S is in kinase domain—structural mechanism for membrane affinity change unexplained PMID:31511666
  • S1292 evidence is indirect marker of membrane association, not direct mechanism PMID:25485852

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). G2019S Amplifies Lysosomal Volume-Sensing Through Membrane Microdomain Partitio…. SciDEX hypothesis. https://prism.scidex.ai/hypotheses/h-36d21444fd

BibTeX 
@misc{scidex_hypothesis_h36d2144,
  title        = {G2019S Amplifies Lysosomal Volume-Sensing Through Membrane Microdomain Partitio…},
  author       = {etl-backfill},
  year         = {2026},
  howpublished = {SciDEX hypothesis},
  url          = {https://prism.scidex.ai/hypotheses/h-36d21444fd},
  note         = {SciDEX artifact hypothesis:h-36d21444fd}
}

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