Kinase activity of mutant LRRK2 mediates neuronal toxicity.
Mutations in the the leucine-rich repeat kinase-2 (LRRK2) gene cause autosomal-dominant Parkinson disease and some cases of sporadic Parkinson disease. Here we found that LRRK2 kinase activity was regulated by GTP via the intrinsic GTPase Roc domain, and alterations of LRRK2 protein that reduced kinase activity of mutant LRRK2 correspondingly reduced neuronal toxicity. These data elucidate the pathogenesis of LRRK2-linked Parkinson disease, potentially illuminate mechanisms of sporadic Parkinson disease and suggest therapeutic targets.
Smith
Wanli W
WW
Department of Psychiatry, Division of Neurobiology, Johns Hopkins University School of Medicine, CMSC 8-121, 600 North Wolfe Street, Baltimore, Maryland 21287, USA. wsmith60@jhmi.edu
Pei
Zhong
Z
Jiang
Haibing
H
Dawson
Valina L
VL
Dawson
Ted M
TM
Ross
Christopher A
CA
D000704:Analysis of Variance; D015153:Blotting, Western / Q000379:methods; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D049452:Green Fluorescent Proteins / Q000096:biosynthesis; D006160:Guanosine Triphosphate / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D020287:In Situ Nick-End Labeling / Q000379:methods; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D016296:Mutagenesis / Q000502:physiology; D009154:Mutation; D009447:Neuroblastoma; D009474:Neurons / Q000187:drug effects / Q000201:enzymology*; D020258:Neurotoxicity Syndromes / Q000201:enzymology* / Q000235:genetics; D010770:Phosphotransferases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D014162:Transfection / Q000379:methods
D049452:Green Fluorescent Proteins; D006160:Guanosine Triphosphate; D010770:Phosphotransferases; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases