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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

Parkinson's disease-associated mutations in LRRK2 link enhanced GTP-binding and kinase activities to neuronal

Andrew B West1, Darren J Moore, Catherine Choi

  • 1Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

Human Molecular Genetics
|January 4, 2007
PubMed

Insights

Mutations in leucine-rich repeat kinase 2 (LRRK2) increase its kinase activity, driving neurodegeneration in Parkinson's disease. Both LRRK2 kinase and GTPase activities are essential for this toxicity.

Area of Science:

  • Neuroscience
  • Genetics
  • Molecular Biology

Background:

  • Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are a significant cause of late-onset Parkinson's disease.
  • The precise mechanisms by which LRRK2 alterations lead to neurodegeneration are not fully understood.

Purpose of the Study:

  • To investigate the functional consequences of LRRK2 mutations on its kinase and GTPase activities.
  • To elucidate the relationship between LRRK2's enzymatic activities and its role in neurotoxicity.

Main Methods:

  • Assessed kinase activity for 10 familial Parkinson's disease-associated LRRK2 mutations.
  • Examined the interplay between LRRK2's guanosine triphosphatase (GTPase) and kinase activities.
  • Evaluated the necessity of LRRK2 kinase and GTPase activities for neurotoxicity in cellular models.

Main Results:

  • Seven of 10 familial LRRK2 mutations showed increased kinase activity.
  • LRRK2 kinase activity is dependent on its GTPase activity, but GTPase activity can function independently.
  • Both LRRK2 kinase and GTPase activities are required for neurotoxicity and potentiation of peroxide-induced cell death.

Conclusions:

  • LRRK2 kinase activity is directly linked to pathogenic mechanisms in Parkinson's disease.
  • These findings support a gain-of-function model for LRRK2 mutations in neurodegeneration.
  • Understanding LRRK2's enzymatic functions provides insights into Parkinson's disease pathogenesis.

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