Smith Wanli W, Pei Zhong, Jiang Haibing, Dawson Valina L, Dawson Ted M, Ross Christopher A
Department of Psychiatry, Division of Neurobiology, Johns Hopkins University School of Medicine, CMSC 8-121, 600 North Wolfe Street, Baltimore, Maryland 21287, USA.
Nat Neurosci. 2006 Oct;9(10):1231-3. doi: 10.1038/nn1776. Epub 2006 Sep 17.
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.
富含亮氨酸重复激酶2（LRRK2）基因的突变会导致常染色体显性帕金森病以及一些散发性帕金森病病例。在此我们发现，LRRK2激酶活性通过内在的GTP酶Roc结构域受GTP调控，而降低突变型LRRK2激酶活性的LRRK2蛋白改变相应地降低了神经元毒性。这些数据阐明了LRRK2相关帕金森病的发病机制，可能揭示散发性帕金森病的机制并提示治疗靶点。
