PLoS ONE (Dec 2009)

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

DOI
https://doi.org/10.1371/journal.pone.0008463
Journal volume & issue
Vol. 4, no. 12
p. e8463

Abstract

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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.