Related Experiment Video

Updated: May 16, 2025

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

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PPM1M, a LRRK2-counteracting, phosphoRab12-preferring phosphatase with potential link to Parkinson's disease

Claire Y Chiang1,2, Neringa Pratuseviciute3, Yu-En Lin1,2

  • 1Department of Biochemistry, Stanford University School of Medicine; Stanford, USA.

Biorxiv : the Preprint Server for Biology
|April 1, 2025
PubMed

Insights

Leucine-rich repeat kinase 2 (LRRK2) pathway phosphatases are crucial in Parkinson's disease. This study identifies PPM1M as a key phosphatase in this pathway, offering a potential therapeutic target.

Area of Science:

  • Molecular biology
  • Neuroscience
  • Biochemistry

Background:

  • Leucine-rich repeat kinase 2 (LRRK2) activating mutations are linked to Parkinson's disease.
  • LRRK2 phosphorylates Rab GTPases, impacting receptor trafficking.
  • Phosphatases like PPM1H reverse Rab phosphorylation.

Purpose of the Study:

  • To identify phosphatases involved in the LRRK2 signaling pathway.
  • To characterize the function and selectivity of PPM1M.
  • To investigate the role of PPM1M in Parkinson's disease pathogenesis.

Main Methods:

  • A phosphatome-wide siRNA screen was employed.
  • Cellular and mouse models were used for knockout studies.
  • In vitro and cellular assays tested PPM1M mutation activity.

Main Results:

  • PPM1M was identified as a phosphatase with preference for phosphoRab12, also acting on phosphoRab8A and phosphoRab10.
  • PPM1M knockout in cells and mice showed selectivity for phosphoRab12.
  • Ppm1m knockout in mice led to primary cilia loss in striatal cholinergic interneurons.
  • A rare, catalytically inactive PPM1M mutation was found in Parkinson's disease patients.

Conclusions:

  • PPM1M is a key phosphatase in the LRRK2 signaling pathway.
  • PPM1M plays a role in primary cilia integrity in neurons.
  • PPM1M represents a potential therapeutic target for Parkinson's disease.

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