Molecular and Cellular Analysis of DJ-1 Function

描述（由申请人提供）：帕金森病（PD）是一种缓慢进展但破坏性的神经退行性疾病，折磨着超过100万美国人。帕金森氏症的病因是一个特别具有挑战性的问题，这在很大程度上是因为疾病病程漫长。病理研究表明细胞氧化应激或蛋白质错误折叠与帕金森病有关。对家族性、遗传性帕金森病的几个基因的鉴定，使帕金森病的分子治疗成为可能。最近，发现DJ-1基因突变可导致常染色体隐性遗传，早发性帕金森病。dj -1相关家族性PD的临床病史是该疾病的典型，包括静息性震颤、强直、步态困难和对左旋多巴治疗的反应性。脑功能神经影像学显示突触前多巴胺缺失与帕金森病一致。DJ-1的正常细胞功能尚不清楚，但DJ-1在脊椎动物中的普遍表达以及不同物种中DJ-1同源物的高度保守性表明，DJ-1具有重要的细胞功能。DJ-1同源物涉及多种生物化学和细胞作用，包括蛋白酶、氨基转移酶、过氧化氢酶和伴侣活性，使DJ-1功能的解释复杂化。DJ-1及其同源物的表达可诱导细胞应激反应，提示DJ-1突变与PD病理之间可能存在联系。我们的初步数据表明，DJ-1是一种氧化还原依赖的分子伴侣，在细胞对氧化应激的反应中起重要作用。我们建议利用互补的生化、细胞和小鼠遗传方法来研究DJ-1活性的机制。

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a slowly progressive but devastating neurodegenerative disorder that afflicts over 1 million Americans. The etiology of Parkinson's disease has posed a particularly challenging problem to investigate, in large part because of the lengthy disease course. Pathological studies have correlated cellular oxidative stress or protein misfolding with PD. The identification of several genes that underlie familial, inherited forms of PD has allowed for a molecular approach to PD. Recently, mutations in DJ-1 have been found to lead to autosomal recessive, early onset PD. The clinical history of DJ-1-associated familial PD is typical of the disease, including rest tremor, rigidity, gait difficulty, and responsiveness to levodopa treatment. Functional neuroimaging of the brain reveals a presynaptic dopamine deficit consistent with PD. The normal cellular function of DJ-1 is unknown, but the ubiquitous expression of DJ-1 in vertebrates and the high degree of conservation among DJ-1 homologues among diverse species suggest that DJ-1 subserves important cellular functions. DJ-1 homologues have been implicated in several biochemical and cellular roles including protease, amidotransferase, catalase, and chaperone activities, complicating the interpretation of DJ-1 function. The expression of DJ-1 and homologues is induced ii cellular stress responses, suggesting a possible link between DJ-1 mutation and PD pathology. Our preliminary data indicate that DJ-1 is a redox-dependent molecular chaperone that plays an important role in the cellular response to oxidative stress. We propose to investigate the mechanism of DJ-1 activity using complementary biochemical, cellular, and mouse genetic approaches.