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，困扰着超过100万美国人。帕金森氏病的病因学已经提出了一个特别具有挑战性的问题进行调查，在很大程度上是因为漫长的病程。病理学研究已经将细胞氧化应激或蛋白质错误折叠与PD相关联。确定了几个基因的基础家族，遗传形式的PD允许的分子方法PD。最近，已发现DJ-1突变导致常染色体隐性遗传的早发性PD。DJ-1相关家族性PD的临床病史是该疾病的典型特征，包括静息震颤、强直、步态困难和对左旋多巴治疗的反应性。脑功能性神经影像学显示突触前多巴胺缺乏与PD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DJ-1同源物在不同物种中的高度保守性表明DJ-1具有重要的细胞功能。DJ-1同源物涉及几种生物化学和细胞作用，包括蛋白酶、酰胺转移酶、过氧化氢酶和分子伴侣活性，使DJ-1功能的解释复杂化。DJ-1和同源物的表达是由细胞应激反应诱导的，这表明DJ-1突变和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性分子伴侣，在细胞对氧化应激的反应中起着重要作用。我们建议使用互补的生化，细胞和小鼠遗传学方法来研究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.