Leucine-rich repeat kinase 2 mutations and Parkinson's disease: three questions

ASN Neuro. 2009 Apr 14;1(1):e00002. doi: 10.1042/AN20090007.


Mutations in the gene encoding LRRK2 (leucine-rich repeat kinase 2) were first identified in 2004 and have since been shown to be the single most common cause of inherited Parkinson's disease. The protein is a large GTP-regulated serine/threonine kinase that additionally contains several protein-protein interaction domains. In the present review, we discuss three important, but unresolved, questions concerning LRRK2. We first ask: what is the normal function of LRRK2? Related to this, we discuss the evidence of LRRK2 activity as a GTPase and as a kinase and the available data on protein-protein interactions. Next we raise the question of how mutations affect LRRK2 function, focusing on some slightly controversial results related to the kinase activity of the protein in a variety of in vitro systems. Finally, we discuss what the possible mechanisms are for LRRK2-mediated neurotoxicity, in the context of known activities of the protein.

Publication types

  • Review

MeSH terms

  • Animals
  • Humans
  • Intermediate Filament Proteins / genetics
  • Intermediate Filament Proteins / metabolism
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Mutation / genetics*
  • Parkinson Disease / enzymology*
  • Parkinson Disease / genetics*
  • Parkinson Disease / pathology
  • Protein Interaction Domains and Motifs / genetics
  • Protein-Serine-Threonine Kinases / genetics*
  • Protein-Serine-Threonine Kinases / metabolism


  • Intermediate Filament Proteins
  • desmuslin
  • LRRK2 protein, human
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Protein-Serine-Threonine Kinases