Related Experiment Video

Updated: May 16, 2026

Assaying the Kinase Activity of LRRK2 in vitro
06:09

Assaying the Kinase Activity of LRRK2 in vitro

Published on: January 18, 2012

Regulation between LRRK2 and PP2A signaling in cellular models of Parkinson's disease

Panagiotis S Athanasopoulos1, Anna Memou2, Franz Y Ho1

  • 1Department of Cell Biochemistry, University of Groningen, Nijenborgh 7, 9747 AG Groningen, The Netherlands.

The Biochemical Journal
|May 14, 2026
PubMed

Insights

Leucine-rich repeat kinase 2 (LRRK2) mutations drive Parkinson's disease (PD). This study reveals LRRK2 phosphorylates Protein phosphatase 2A (PP2A), impairing its function and contributing to neuronal death in PD.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Biochemistry

Background:

  • Mutations in Leucine-rich repeat kinase 2 (LRRK2) are a primary genetic cause of Parkinson's disease (PD).
  • Increased LRRK2 kinase activity is implicated in idiopathic PD pathogenesis, independent of mutations.
  • The precise mechanisms of LRRK2 activation and its link to neuronal death remain incompletely understood.

Purpose of the Study:

  • To elucidate the role of LRRK2-phosphatase interactions in PD pathogenesis.
  • To investigate the impact of LRRK2 on Protein phosphatase 2A (PP2A) activity and holoenzyme formation.
  • To determine if LRRK2-mediated PP2A modification contributes to LRRK2-associated neurodegeneration.

Main Methods:

  • In vitro biochemical assays to assess LRRK2-PP2A interactions and phosphorylation.
  • Analysis of LRRK2 dimer stability and kinase activity upon PP2A dephosphorylation.
  • Site-directed mutagenesis of PP2A catalytic subunit (PPP2CA) at threonine 304 (T304).
  • Neuronal cell culture models expressing wild-type (WT) and mutant LRRK2 and PP2CA.

Main Results:

  • Protein phosphatase 2A (PP2A) dephosphorylates LRRK2 within the RocCOR-GTPase domain, destabilizing dimers and reducing kinase activity.
  • LRRK2 phosphorylates PPP2CA at T304, altering its C-terminal methylation and affecting holoenzyme formation and activity.
  • Expression of WT-PPP2CA conferred protection against LRRK2-G2019S-induced neuronal cell death, whereas PPP2CA-T304 mutants did not.

Conclusions:

  • LRRK2 directly regulates PP2A activity through phosphorylation at T304.
  • Impaired PP2A holoenzyme formation due to LRRK2-mediated phosphorylation may be a critical factor in LRRK2-PD pathogenesis.
  • Targeting the LRRK2-PP2A interaction could offer a novel therapeutic strategy for Parkinson's disease.
Keywords:
LRRK2PP2AParkinsons diseasePhosphatasekinase

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