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The Emerging Functions of LRRK2 and Rab GTPases in the Endolysosomal System

Tomoki Kuwahara1, Takeshi Iwatsubo1

  • 1Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Frontiers in Neuroscience
|April 8, 2020
PubMed

Insights

Leucine-rich repeat kinase 2 (LRRK2) mutations are linked to Parkinson's disease. LRRK2 regulates cellular waste disposal via the endolysosomal system, and its dysfunction may drive disease pathology.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Genetics

Background:

  • Leucine-rich repeat kinase 2 (LRRK2) is the most common genetic cause of autosomal-dominant Parkinson's disease.
  • LRRK2 mutations enhance its kinase activity, particularly its phosphorylation of Rab GTPases.
  • LRRK2 is implicated in intracellular vesicle trafficking and organelle homeostasis.

Purpose of the Study:

  • To review recent advances on the role of LRRK2 and Rab GTPases in the endolysosomal system.
  • To explore the connection between LRRK2-mediated endolysosomal regulation and Parkinson's disease pathogenesis.

Main Methods:

  • Literature review of cell biological studies and genetic findings.
  • Analysis of LRRK2 phosphorylation targets (Rab GTPases) and their cellular functions.
  • Examination of lysosomal and endosomal morphology in LRRK2 knockout/inhibition models and patient cells.

Main Results:

  • LRRK2 regulates key aspects of the endolysosomal system, including vesicle trafficking and organelle maintenance.
  • Parkinson's-associated LRRK2 mutations enhance Rab phosphorylation, potentially disrupting endolysosomal function.
  • Lysosomal abnormalities are observed in various models with LRRK2 genetic manipulation and in cells from Parkinson's patients with LRRK2 mutations.

Conclusions:

  • LRRK2 plays a critical role in maintaining endolysosomal system integrity.
  • Dysregulation of LRRK2 kinase activity and its impact on Rab GTPases are mechanistically linked to Parkinson's disease.
  • Targeting LRRK2 or its downstream pathways may offer therapeutic strategies for Parkinson's disease.
Keywords:
LRRK2Rabendosomelysosomephosphorylationtrafficking

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