Molecular analysis of DJ-1 function and dysfunction

尽管帕金森氏病(PD)已被发现近两个世纪，但其分子机制 帕金森病的发病机制仍然知之甚少，目前还没有治愈方法来阻止 这种毁灭性疾病的发展。稀有基因产物的分子特征 家族性帕金森病有助于描绘与神经变性相关的致病途径 常见的散发性帕金森病。最近，DJ-1的缺失和错义突变被鉴定为 早发性常染色体隐性遗传性家族性帕金森病的遗传缺陷。此外，DJ-1被发现 定位于Picks病、阿尔茨海默病、路易体病理性tau包涵体的一个子集 痴呆症、进行性核上性瘫痪和与帕金森病相关的额颞部痴呆 17号染色体。然而，目前对DJ-1的生物学功能以及DJ-1如何 突变会导致神经退化。在这个项目中，申请者将使用生化、细胞 解决以下问题的生物学、蛋白质组和分子遗传学方法：什么是 DJ-1的生化功能？DJ-1是否与α-突触核蛋白、parkin和 UCH-L1或在不同于这些其他家族性PD基因的不同途径？帕金森氏症相关的误解是如何 突变会影响DJ-1的结构和功能以及神经元存活吗？DJ-1是否被不可逆转地氧化成 特发性警局？如果是这样的话，DJ-1的氧化损伤是否与散发性帕金森病的发病有关 家族性帕金森病的致病方式与DJ-1基因突变相似？这些问题的答案不仅会 提高我们对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 洞察DJ-1突变导致神经变性的分子机制。完成 该项目将促进我们对帕金森病发病机制的了解，并加快努力 探索帕金森病和相关神经退行性疾病的治疗方法。

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.