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Assaying the Kinase Activity of LRRK2 in vitro
06:09

Assaying the Kinase Activity of LRRK2 in vitro

Published on: January 18, 2012

The familial Parkinsonism gene LRRK2 regulates neurite process morphology

David MacLeod1, Julia Dowman, Rachel Hammond

  • 1Departments of Pathology and Neurology, Center for Neurobiology and Behavior and Taub Institute, Columbia University, College of Physicians and Surgeons 15-403, 630 West 168th Street, New York, New York 10032, USA.

Neuron
|November 23, 2006
PubMed

Insights

Mutations in Leucine-Rich Repeat Kinase 2 (LRRK2) cause inherited Parkinson's disease (PD) by increasing its kinase activity. This leads to reduced neurite growth and neuronal death, mimicking sporadic PD.

Area of Science:

  • Neuroscience
  • Genetics
  • Molecular Biology

Background:

  • Mutations in Leucine-Rich Repeat Kinase 2 (LRRK2) are linked to autosomal-dominant inherited Parkinson's disease (PD).
  • The precise function of LRRK2 protein domains, including kinase and repeat regions, remains largely unknown.
  • LRRK2 mutations clinically resemble common sporadic Parkinson's disease.

Purpose of the Study:

  • To investigate the functional impact of Parkinson's disease-associated LRRK2 mutations.
  • To determine the role of LRRK2 kinase activity in neuronal morphology and survival.
  • To explore the cellular consequences of LRRK2 mutations in neuronal models.

Main Methods:

  • Analysis of LRRK2 kinase activity in cells expressing PD-associated mutations.
  • Assessment of neurite length and branching in primary neuronal cultures.
  • In vivo studies using rodent central nervous system (CNS) models.
  • Examination of cellular inclusions and neuronal apoptosis.

Main Results:

  • PD-associated LRRK2 mutations result in disinhibited kinase activity.
  • Mutant LRRK2 expression progressively reduces neurite length and branching in neuronal cultures and the rodent CNS.
  • LRRK2 deficiency conversely increases neurite outgrowth.
  • Neurons expressing mutant LRRK2 exhibit phospho-tau-positive inclusions and undergo apoptosis.

Conclusions:

  • Disinhibited LRRK2 kinase activity is a key pathogenic mechanism in familial Parkinson's disease.
  • LRRK2 mutations disrupt neuronal development and survival, contributing to PD pathogenesis.
  • Aberrant LRRK2 function leads to cellular pathology, including tau aggregation and neuronal death.

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