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Updated: Jul 25, 2025

Assaying the Kinase Activity of LRRK2 in vitro
06:09

Assaying the Kinase Activity of LRRK2 in vitro

Published on: January 18, 2012

22.6K

Regulation of LRRK2 mRNA stability by ATIC and its substrate AICAR through ARE-mediated mRNA decay in Parkinson's

Qinfang Liu1, Dong Zhu1, Naren Li2

  • 1Department of Neuroscience, University of Connecticut School of Medicine, Farmington, CT, USA.

The EMBO Journal
|June 27, 2023
PubMed

Insights

AICAr regulates Parkinson

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Mutations in Leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson's disease (PD).
  • Both LRRK2 enzymatic activity and elevated LRRK2 protein levels are implicated in PD pathogenesis.
  • Mechanisms regulating LRRK2 protein levels are not fully understood.

Purpose of the Study:

  • To investigate the role of the purine biosynthesis enzyme ATIC in regulating LRRK2 levels and toxicity.
  • To elucidate the mechanism by which AICAr affects LRRK2 expression and PD-related pathology.

Main Methods:

  • Investigated the effect of AICAr on LRRK2 levels in vitro and in mouse models.
  • Examined the role of AUF1-mediated mRNA decay in LRRK2 regulation.
  • Assessed LRRK2-induced neurodegeneration and neuroinflammation in Drosophila and mouse models of PD.

Main Results:

  • AICAr, a precursor for ATIC substrate, regulates LRRK2 protein levels in a cell-type-specific manner.
  • AICAr induces LRRK2 mRNA decay via recruitment of AUF1 to AU-rich elements (AREs), leading to DCP1/2 complex recruitment.
  • AICAr treatment suppressed LRRK2 expression and rescued LRRK2-induced neurodegeneration and neuroinflammation in PD models.

Conclusions:

  • Identified a novel regulatory mechanism for LRRK2 protein levels through AICAr-mediated mRNA decay.
  • This mechanism is independent of LRRK2 enzymatic activity and offers a new therapeutic target for Parkinson's disease.
  • AICAr demonstrates potential in rescuing LRRK2-associated neurotoxicity and neuroinflammation.
Keywords:
AICARAUF1LRRK2Parkinson's diseasemRNA decay

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