Related Experiment Video

Updated: Aug 5, 2026

Rab10 Phosphorylation Detection by LRRK2 Activity Using SDS-PAGE with a Phosphate-binding Tag
08:55

Rab10 Phosphorylation Detection by LRRK2 Activity Using SDS-PAGE with a Phosphate-binding Tag

Published on: December 14, 2017

The LRRK2 G2019S variant rewires Rab GTPase phosphorylation after lysosomal damage and promotes cell death in human

Rebecca Morrison1, Simeon R Mihaylov2, Chak Hon Luk1

  • 1Host-Pathogen Interactions in Tuberculosis Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.

Journal of Cell Science
|July 27, 2026
PubMed

Insights

The LRRK2 G2019S variant, common in Parkinson's disease, alters immune cell function. It increases macrophage susceptibility to cell death after lysosomal damage through a kinase-independent mechanism.

Area of Science:

  • Neuroscience
  • Immunology
  • Genetics

Background:

  • Leucine-rich repeat kinase 2 (LRRK2) variants are the primary genetic cause of Parkinson's disease.
  • The precise impact of these variants on immune cell function, particularly macrophages, is not fully understood.

Purpose of the Study:

  • To investigate how the pathogenic LRRK2 G2019S variant influences macrophage responses to lysosomal damage.
  • To elucidate the kinase-dependent and kinase-independent mechanisms involved.

Main Methods:

  • Utilized phosphoproteomic analysis to examine LRRK2-dependent Rab GTPase phosphorylation.
  • Generated isogenic induced pluripotent stem cells from patients with the LRRK2 G2019S variant.
  • Assessed macrophage susceptibility to apoptosis following lysosomal damage.

Main Results:

  • LRRK2 G2019S selectively altered Rab GTPase phosphorylation, increasing Rab12 and decreasing Rab35 phosphorylation upon lysosomal damage.
  • Macrophages with the LRRK2 G2019S variant exhibited heightened susceptibility to apoptosis after lysosomal damage.
  • This increased cell death was independent of LRRK2 kinase activity, suggesting a kinase-independent role in cell survival.

Conclusions:

  • The LRRK2 G2019S variant dysregulates macrophage response to lysosomal damage.
  • This variant impacts Rab GTPase phosphorylation and promotes cell death via a kinase-independent pathway.
  • Findings suggest a novel role for LRRK2 in regulating immune cell survival.
Keywords:
ApoptosisLRRK2Lysosomal damageMacrophageParkinson's diseaseRab GTPase

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