Molecular analysis of DJ-1 function and dysfunction

DJ-1 功能和功能障碍的分子分析

• 批准号: 7048136
• 负责人: Lih-Shen Chin
• 金额: $ 34.43万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7048136
• 关键词: endopeptidases; gene mutation; genes; genetics; lead; neural degeneration; point mutation; role; stress; endopeptidases; gene mutation; genes; genetics; lead; neural degeneration; point mutation; role; stress

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.

描述（由申请人提供）：尽管帕金森氏病（PD）已有近两个世纪以来，但PD发病机理的分子机制仍然很熟悉，目前尚无治愈方法来阻止这种毁灭性疾病的发展。 PD罕见家族形式的基因产物的分子表征可以帮助描绘PD的常见零星形式中与神经变性相关的致病途径。最近，DJ-1中的缺失和错义突变被确定为家族性PD的早期发作，常染色体隐性形式的遗传缺陷。此外，发现DJ-1位于Picks疾病，阿尔茨海默氏病，Lewy身体痴呆症，进行性性痴呆症和额颞痴呆与帕金森氏症中的一部分中，与17号染色​​体相关的DJ-1 JJ-1-1-1-1-1-1-1-1-1-1-1-1-1-1-1-1-1-1-1-1-1-1-1-1-1-1-1-1-1-1-1-1-1-1-1-1-1-1.在该项目中，申请人将使用生化，细胞生物学，蛋白质组学和分子遗传学方法的结合来解决以下问题：DJ-1的生化功能是什么？ DJ-1是否在类似的细胞途径中起作用与α-突触核蛋白，Parkin和UCH-L1，或在与这些其他家族性PD基因不同的不同途径中起作用？ PD连接的错义突变如何影响DJ-1和神经元存活的结构和功能？ DJ-1是否在特发性PD中不可逆地氧化？如果是这样，对DJ-1的氧化损害是否以类似于引起家族性PD的DJ-1基因突变的方式有助于零星PD的发病机理？这些问题的答案不仅会提高我们对DJ-1在神经元生理学中的正常功能的了解，而且还应对DJ-1突变导致神经变性的分子机制产生新的见解。拟议项目的完成应提高我们对PD发病机理的理解，并加快发现PD和相关神经退行性疾病的治愈疗法的努力。