The WD40 domain is required for LRRK2 neurotoxicity

Nathan D. Jorgensen, Yong Peng, Cherry C.Y. Ho, Hardy J. Rideout, Donald Petrey, Peng Liu, William T. Dauer

Research output: Contribution to journalArticlepeer-review

72 Scopus citations

Abstract

Background: Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson disease (PD). LRRK2 contains an "enzymatic core" composed of GTPase and kinase domains that is flanked by leucine-rich repeat (LRR) and WD40 protein-protein interaction domains. While kinase activity and GTP-binding have both been implicated in LRRK2 neurotoxicity, the potential role of other LRRK2 domains has not been as extensively explored. Principal Findings: We demonstrate that LRRK2 normally exists in a dimeric complex, and that removing the WD40 domain prevents complex formation and autophosphorylation. Moreover, loss of the WD40 domain completely blocks the neurotoxicity of multiple LRRK2 PD mutations. Conclusion: These findings suggest that LRRK2 dimerization and autophosphorylation may be required for the neurotoxicity of LRRK2 PD mutations and highlight a potential role for the WD40 domain in the mechanism of LRRK2- mediated cell death.

Original languageEnglish (US)
Article numbere8463
JournalPloS one
Volume4
Issue number12
DOIs
StatePublished - 2009

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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