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Assaying the Kinase Activity of LRRK2 in vitro
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Assaying the Kinase Activity of LRRK2 in vitro

Published on: January 18, 2012

Leucine-rich repeat kinase 2 and alternative splicing in Parkinson's disease

David A Elliott1, Woojin S Kim, Sarsha Gorissen

  • 1Neuroscience Research Australia, Barker St., Randwick, Sydney, NSW 2031, Australia.

Movement Disorders : Official Journal of the Movement Disorder Society
|April 25, 2012
PubMed

Insights

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are linked to Parkinson's disease (PD). This study found LRRK2 influences alternative splicing in neurodegeneration genes, suggesting RNA metabolism alterations contribute to PD.

Area of Science:

  • Neuroscience
  • Genetics
  • Molecular Biology

Background:

  • Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common genetic cause of Parkinson's disease (PD).
  • LRRK2 mutations are associated with diverse neuropathological findings.
  • The precise mechanisms by which LRRK2 mutations contribute to PD pathogenesis remain incompletely understood.

Purpose of the Study:

  • To investigate the hypothesis that LRRK2 mediates its pathogenic effects through alternative splicing of neurodegeneration-associated genes.
  • To explore the role of LRRK2 in regulating gene expression and RNA splicing patterns relevant to Parkinson's disease.

Main Methods:

  • Western blotting to analyze subcellular protein fractions.
  • Exon-array analysis of RNA from neuroblastoma cells transfected with LRRK2 expression vectors.
  • Reverse-transcription polymerase chain reaction (RT-PCR) on cultured cells and postmortem Parkinson's disease brain tissue.

Main Results:

  • Overexpression of LRRK2 (G2019S mutant) significantly decreased nuclear transactive response DNA-binding protein 43 (TRDDPB) levels.
  • LRRK2 significantly affected the expression of genes involved in nuclear functions and cell-cycle regulation.
  • Altered splicing of microtubule-associated protein tau (MAPT) and alpha-synuclein (SNCA) genes was observed upon LRRK2 overexpression, and in postmortem PD brains.

Conclusions:

  • Aberrant RNA metabolism, specifically altered alternative splicing, is implicated as a significant contributor to idiopathic Parkinson's disease.
  • LRRK2 plays a role in regulating RNA splicing of key genes associated with neurodegeneration.
  • These findings highlight potential therapeutic targets within RNA processing pathways for Parkinson's disease treatment.

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