Molecular analysis of DJ-1 function and dysfunction

描述（由申请人提供）：尽管帕金森病（PD）已被发现近两个世纪，但其发病机制的分子机制仍然知之甚少，目前还没有治愈方法来阻止这种毁灭性疾病的进展。罕见家族性帕金森病基因产物的分子特征可以帮助描述与常见散发性帕金森病神经退行性变相关的致病途径。最近，DJ-1的缺失和错义突变被确定为早发性常染色体隐性家族性帕金森病的遗传缺陷。此外，DJ-1被发现定位于与17号染色体相关的匹克病、阿尔茨海默病、路易体痴呆、进行性核上性麻痹和额颞叶痴呆伴帕金森病的病理性tau包涵体亚群中。然而，目前对DJ-1的生物学功能以及DJ-1突变如何引起神经变性知之甚少。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的组合来解决以下问题：DJ-1的生化功能是什么？DJ-1是在与α -突触核蛋白、帕金蛋白和UCH-L1相似的细胞途径中起作用，还是在与其他家族性PD基因不同的不同途径中起作用？pd相关的错义突变如何影响DJ-1的结构和功能以及神经元的存活？DJ-1在特发性PD中是否被不可逆氧化？如果是这样，DJ-1的氧化损伤是否以类似于DJ-1基因突变导致家族性PD的方式导致散发性PD的发病机制？这些问题的答案不仅将促进我们对DJ-1在神经生理学中的正常功能的了解，而且还将对DJ-1突变导致神经退行性变的分子机制产生新的见解。该项目的完成将促进我们对帕金森病发病机制的理解，并加速发现帕金森病及相关神经退行性疾病的治疗方法。

DESCRIPTION (provided by applicant): 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.