Parkinson's disease-associated mutations in LRRK2 link enhanced GTP-binding and kinase activities to neuronal toxicity.
Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) cause late-onset Parkinson's disease indistinguishable from idiopathic disease. The mechanisms whereby missense alterations in the LRRK2 gene initiate neurodegeneration remain unknown. Here, we demonstrate that seven of 10 suspected familial-linked mutations result in increased kinase activity. Functional and disease-associated mutations in conserved residues reveal the critical link between intrinsic guanosine triphosphatase (GTPase) activity and downstream kinase activity. LRRK2 kinase activity requires GTPase activity, whereas GTPase activity functions independently of kinase activity. Both LRRK2 kinase and GTPase activity are required for neurotoxicity and potentiate peroxide-induced cell death, although LRRK2 does not function as a canonical MAP-kinase-kinase-kinase. These results suggest a link between LRRK2 kinase activity and pathogenic mechanisms relating to neurodegeneration, further supporting a gain-of-function role for LRRK2 mutations.
West
Andrew B
AB
Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Moore
Darren J
DJ
Choi
Catherine
C
Andrabi
Shaida A
SA
Li
Xiaojie
X
Dikeman
Dustin
D
Biskup
Saskia
S
Zhang
Zhenshui
Z
Lim
Kah-Leong
KL
Dawson
Valina L
VL
Dawson
Ted M
TM
D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D051379:Mice; D009154:Mutation / Q000235:genetics*; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects; D010300:Parkinson Disease / Q000235:genetics* / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism* / Q000633:toxicity
C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases; D020558:GTP Phosphohydrolases