Cell Biology and Gene Expression Unit, Laboratory of Neurogenetics, NIA, National Institutes of Health, Bethesda, MD, USA.
Laboratory for Neurobiology and Gene Therapy, Division of Molecular Medicine, Department of Molecular and Cellular Medicine, Katholieke Universiteit Leuven, Leuven, Belgium.
Bioessays. 2010 Mar;32(3):227-235. doi: 10.1002/bies.200900163.
Parkinson's disease (PD) is generally sporadic but a number of genetic diseases have parkinsonism as a clinical feature. Two dominant genes, alpha-synuclein (SNCA) and leucine-rich repeat kinase 2 (LRRK2), are important for understanding inherited and sporadic PD. SNCA is a major component of pathologic inclusions termed Lewy bodies found in PD. LRRK2 is found in a significant proportion of PD cases. These two proteins may be linked as most LRRK2 PD cases have SNCA-positive Lewy bodies. Mutations in both proteins are associated with toxic effects in model systems although mechanisms are unclear. LRRK2 is an intracellular signaling protein possessing both GTPase and kinase activities that may contribute to pathogenicity. A third protein, tau, is implicated as a risk factor for PD. We discuss the potential relationship between these genes and suggest a model for PD pathogenesis where LRRK2 is upstream of pathogenic effects through SNCA, tau, or both proteins.
帕金森病（PD）通常是散发性的，但有一些遗传性疾病以帕金森病为临床特征。两种显性基因，α-突触核蛋白（SNCA）和富亮氨酸重复激酶 2（LRRK2），对于理解遗传性和散发性 PD 很重要。SNCA 是在 PD 中发现的称为路易体的病理性包涵体的主要成分。LRRK2 在很大比例的 PD 病例中被发现。这两种蛋白质可能有关联，因为大多数 LRRK2 PD 病例有 SNCA 阳性的路易体。这两种蛋白质的突变都与模型系统中的毒性作用有关，尽管机制尚不清楚。LRRK2 是一种具有 GTP 酶和激酶活性的细胞内信号蛋白，可能有助于致病性。第三种蛋白质，tau，被认为是 PD 的危险因素。我们讨论了这些基因之间的潜在关系，并提出了一个 PD 发病机制的模型，其中 LRRK2 通过 SNCA、tau 或这两种蛋白质在致病性影响之前起作用。
