Molecular analysis of DJ-1 function and dysfunction

虽然帕金森病（PD）已经被认识了近两个世纪，但其分子机制仍然是一个未知的问题。 PD的潜在发病机制仍然知之甚少，目前还没有治愈的方法来阻止PD。 这种毁灭性疾病的发展。基因产物的分子特征 家族性PD可以帮助描述与神经变性相关的致病途径， 常见的散发性PD。最近，DJ-1的缺失和错义突变被鉴定为 遗传缺陷的早发性，常染色体隐性形式的家族性PD。此外，发现DJ-1 定位于皮克病、阿尔茨海默病、路易体中的病理性tau包涵体的子集内 痴呆、进行性核上性麻痹和额颞叶痴呆伴帕金森综合征， 17号染色体。然而，目前对DJ-1的生物学功能以及DJ-1如何在细胞内表达和调节细胞凋亡的机制知之甚少。 突变导致神经退化在这个项目中，申请人将使用生物化学，细胞 生物学、蛋白质组学和分子遗传学方法来解决以下问题： DJ-1的生化功能？DJ-1是否与α-突触核蛋白、帕金蛋白和 UCH-L1或在不同的途径不同于这些其他家族性PD基因？PD相关的错义是如何 突变影响DJ-1的结构和功能以及神经元存活？DJ-1是否在 特发性帕金森病？如果是这样的话，DJ-1的氧化损伤是否与帕金森病的发病机制有关？ 与DJ-1基因突变相似的方式导致家族性PD？这些问题的答案不仅 推进我们对DJ-1在神经生理学中的正常功能的认识，但也应该产生新的 深入了解DJ-1突变导致神经退行性变的分子机制。完成 拟议的项目应促进我们对PD发病机制的理解，并加快努力， 发现PD和相关神经退行性疾病的治愈性疗法。

Although Parkinson's disease (PD) has been known for nearly two centuries, the molecular mechanisms underlying the pathogenesis of PD remain poorly understood, and currently there is no cure to stop the progression of this devastating disease. Molecular characterization of the gene products underlying the rare familial forms of PD can help delineate the pathogenic pathways associated with neurodegeneration in the common sporadic forms of PD. Recently, deletion and missense mutations in DJ-1 were identified as the genetic defects for an early-onset, autosomal recessive form of familial PD. Furthermore, DJ-1 was found to localize within a subset of pathological tau inclusions in Picks disease, Alzheimer's disease, Lewy body dementia, progressive supranuclear palsy, and frontotemporal dementia with parkinsonism linked to chromosome 17. However, little is presently known about the biological function of DJ-1 and how DJ-1 mutations cause neurodegeneration. In this project, the applicant will use a combination of biochemical, cell biological, proteomic, and molecular genetic approaches to address the following questions: What is the biochemical function of DJ-1? Does DJ-1 act in a similar cellular pathway as alpha-synuclein, parkin and UCH-L1 or in a different pathway distinct from these other familial PD genes? How do PD-linked missense mutations affect the structure and function of DJ-1 and neuronal survival? Is DJ-1 irreversibly oxidized in idiopathic PD? If so, does oxidative damage to DJ-1 contribute to the pathogenesis of sporadic PD in a manner similar to DJ-1 genetic mutations in causing familial PD? Answers to these questions will not only advance our knowledge about the normal function of DJ-1 in neuronal physiology, but should also yield novel insights into the molecular mechanism by which DJ-1 mutations lead to neurodegeneration. Completion of the proposed project should advance our understanding of PD pathogenesis, and accelerate the efforts to discover curative therapies for PD and related neurodegenerative disorders.