Junn Eunsung, Lee Sang Seop, Suhr Unsun T, Mouradian M Maral
Genetic Pharmacology Unit, Experimental Therapeutics Branch, NINDS, National Institutes of Health, Bethesda, Maryland 20892-1406, USA.
J Biol Chem. 2002 Dec 6;277(49):47870-7. doi: 10.1074/jbc.M203159200. Epub 2002 Oct 2.
Parkinson's disease (PD) is characterized by loss of dopaminergic neurons in the substantia nigra and by the presence of ubiquitinated cytoplasmic inclusions known as Lewy bodies. Alpha-synuclein and Parkin are two of the proteins associated with inherited forms of PD and are found in Lewy bodies. Whereas numerous reports indicate the tendency of alpha-synuclein to aggregate both in vitro and in vivo, no information is available about similar physical properties for Parkin. Here we show that overexpression of Parkin in the presence of proteasome inhibitors leads to the formation of aggresome-like perinuclear inclusions. These eosinophilic inclusions share many characteristics with Lewy bodies, including a core and halo organization, immunoreactivity to ubiquitin, alpha-synuclein, synphilin-1, Parkin, molecular chaperones, and proteasome subunit as well as staining of some with thioflavin S. We propose that the process of Lewy body formation may be akin to that of aggresome-like structures. The tendency of wild-type Parkin to aggregate and form inclusions may have implications for the pathogenesis of sporadic PD.
帕金森病（PD）的特征是黑质中多巴胺能神经元丧失以及存在被称为路易小体的泛素化胞质内含物。α-突触核蛋白和帕金蛋白是与遗传性帕金森病相关的两种蛋白质，且存在于路易小体中。尽管众多报告表明α-突触核蛋白在体外和体内均有聚集倾向，但关于帕金蛋白类似物理特性的信息却尚无报道。在此我们表明，在蛋白酶体抑制剂存在的情况下帕金蛋白的过表达会导致形成聚集体样核周内含物。这些嗜酸性内含物与路易小体具有许多共同特征，包括核心和晕圈结构、对泛素、α-突触核蛋白、突触核蛋白-1、帕金蛋白、分子伴侣和蛋白酶体亚基的免疫反应性，以及部分被硫黄素S染色。我们提出路易小体的形成过程可能类似于聚集体样结构的形成过程。野生型帕金蛋白聚集并形成内含物的倾向可能对散发性帕金森病的发病机制具有重要意义。
