Molecular analysis of DJ-1 function and dysfunction

DJ-1 功能和功能障碍的分子分析

基本信息

批准号：
7759197
负责人：
Lih-Shen Chin
金额：
$ 33.09万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-03-01 至 2013-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7759197
关键词：
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine Address Affect Alzheimer&apos s Disease Behavioral Biochemical Biological Biological Process Brain Cell Survival Cells Cellular Stress Chin Chromosomes, Human, Pair 17 Dimerization Disease Dominant-Negative Mutation Environmental Risk Factor Enzymes Escherichia coli Family Frontotemporal Dementia Functional disorder Gene Mutation Genes Genotype Goals Knockout Mice Knowledge Lead Lewy Body Disease Link Mass Spectrum Analysis Missense Mutation Modification Molecular Molecular Analysis Molecular Chaperones Molecular Genetics Mus Mutation Nature Nerve Degeneration Neurodegenerative Disorders Neuronal Dysfunction Neurons Oxidative Stress PARK7 protein Parkinson Disease Parkinsonian Disorders Pathogenesis Pathway interactions Peptide Hydrolases Phenotype Physiological Physiology Pick Disease of the Brain Point Mutation Predisposition Progressive Supranuclear Palsy Proteins Proteomics Recombinants Research Personnel Role Series Stress Structure Testing Toxic Environmental Substances Toxic effect Two-Dimensional Gel Electrophoresis alpha synuclein base disease-causing mutation dopaminergic neuron early onset functional disability gain of function insight loss of function neuronal survival novel oxidative damage parkin gene/protein programs protein folding protein protein interaction response tau Proteins

项目摘要

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.

尽管帕金森病 (PD) 已为人所知近两个世纪，但其分子机制 PD的发病机制仍知之甚少，目前尚无治愈方法可以阻止PD的发生这种毁灭性疾病的进展。稀有基因产物的分子特征帕金森病的家族性形式可以帮助描述与神经退行性变相关的致病途径 PD 常见的散发形式。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遗传家族性 PD 的遗传缺陷。此外，DJ-1被发现定位于皮克氏病、阿尔茨海默氏病、路易体的病理性 tau 内含物的子集中痴呆、进行性核上性麻痹以及与帕金森病相关的额颞叶痴呆 17 号染色体。然而，目前人们对 DJ-1 的生物学功能以及 DJ-1 如何发挥作用知之甚少。突变导致神经退行性变。在这个项目中，申请人将结合使用生化、细胞生物学、蛋白质组学和分子遗传学方法可以解决以下问题：什么是 DJ-1的生化功能？ DJ-1 的细胞通路是否与 α-突触核蛋白、parkin 和 UCH-L1 或与其他家族性 PD 基因不同的途径？ PD连锁错义是如何发生的突变会影响DJ-1的结构和功能以及神经元的存活吗？ DJ-1 是否被不可逆氧化特发性帕金森病？如果是这样，DJ-1 的氧化损伤是否会导致散发性 PD 的发病机制？与DJ-1基因突变类似的方式导致家族性PD？这些问题的答案不仅增进我们对 DJ-1 在神经元生理学中正常功能的了解，但也应该产生新的成果深入了解 DJ-1 突变导致神经退行性变的分子机制。完成拟议的项目应增进我们对帕金森病发病机制的了解，并加快努力发现帕金森病和相关神经退行性疾病的治疗方法。