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Wild-type LRRK2 but not its mutant attenuates stress-induced cell death via ERK pathway

Anthony K F Liou1, Rehana K Leak, Lihua Li

  • 1Pittsburgh Institute for Neurodegenerative Diseases, Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA. lioukf@upmc.edu

Neurobiology of Disease
|August 5, 2008
PubMed

Insights

Mutations in Leucine-rich repeat kinase 2 (LRRK2) cause Parkinson's disease. Wild-type LRRK2 protects cells from oxidative stress via the ERK pathway, a function lost in LRRK2 mutants.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Leucine-rich repeat kinase 2 (LRRK2) mutations are linked to familial and idiopathic Parkinson's disease.
  • LRRK2 is hypothesized to function as a stress-responsive scaffold regulating mitogen-activated protein kinase (MAPK) pathways.

Purpose of the Study:

  • To investigate the role of wild-type and mutant LRRK2 in cellular response to oxidative stress.
  • To determine if LRRK2's protective effects are mediated by MAPK pathways, specifically ERK.

Main Methods:

  • Utilized HEK293 and SH-SY5Y cell lines expressing wild-type LRRK2 and specific mutants (Y1699C, G2019S).
  • Exposed cells to hydrogen peroxide (H(2)O(2)) to induce oxidative stress.
  • Assessed cell viability and activation of the ERK pathway.

Main Results:

  • Wild-type LRRK2 expression enhanced cellular tolerance to H(2)O(2)-induced oxidative stress.
  • LRRK2 mutants (Y1699C, G2019S) failed to provide this protective effect.
  • The stress tolerance conferred by wild-type LRRK2 was dependent on its kinase domain and involved activation of the ERK pathway.

Conclusions:

  • Cells expressing LRRK2 mutants exhibit a loss of the protective function of wild-type LRRK2 against oxidative stress.
  • This vulnerability to oxidative stress may contribute to the pathogenesis of Parkinson's disease in individuals with LRRK2 mutations.
  • LRRK2's kinase activity and its role in the ERK pathway are crucial for cellular protection against oxidative damage.

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