title: The WD40 domain is required for LRRK2 neurotoxicity.
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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Neurology, Columbia University Medical Center, New York, New York, United States of America.
authors.forename: Nathan D
authors.initials: ND
authors.lastname: Jorgensen
authors.forename: Yong
authors.initials: Y
authors.lastname: Peng
authors.forename: Cherry C-Y
authors.initials: CC
authors.lastname: Ho
authors.forename: Hardy J
authors.initials: HJ
authors.lastname: Rideout
authors.forename: Donald
authors.initials: D
authors.lastname: Petrey
authors.forename: Peng
authors.initials: P
authors.lastname: Liu
authors.forename: William T
authors.initials: WT
authors.lastname: Dauer
mesh_terms: D000818:Animals; D002460:Cell Line; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D008970:Molecular Weight; D009498:Neurotoxins / Q000737:chemistry* / Q000633:toxicity*; D010766:Phosphorylation / Q000187:drug effects; D055503:Protein Multimerization / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry* / Q000633:toxicity*; D017434:Protein Structure, Tertiary; D017384:Sequence Deletion; D040681:Structural Homology, Protein; D013329:Structure-Activity Relationship
chemical_list: D009498:Neurotoxins; D017346:Protein Serine-Threonine Kinases