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：
7579058
负责人：
Lih-Shen Chin
金额：
$ 33.43万
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 2011-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7579058
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.

尽管帕金森氏病（PD）已有近两个世纪的著名，但分子机制 PD的发病机理的基础仍然很少理解，目前尚无治疗方法这种毁灭性疾病的进展。罕见的基因产物的分子表征家族形式的PD可以帮助描述与神经退行性相关的致病途径 PD的常见零星形式。最近，DJ-1中的缺失和错义突变被确定为家族性PD的早期，常染色体隐性形式的遗传缺陷。此外，发现DJ-1 位于病理tau疾病中的病理性tau疾病，阿尔茨海默氏病，路易体内痴呆症，进行性核上麻痹和额颞痴呆与帕金森氏症有关 17染色体。但是，目前对DJ-1的生物学功能以及DJ-1的生物学功能知之甚少突变导致神经变性。在这个项目中，申请人将使用生化，细胞的组合生物学，蛋白质组学和分子遗传学方法来解决以下问题：什么是 DJ-1的生化功能？ DJ-1是否在类似的细胞途径中起作用与α-突触核蛋白，帕金和 UCH-L1或与这些其他家族性PD基因不同的不同途径？ PD连接的错义如何突变会影响DJ-1和神经元存活的结构和功能？在不可逆地氧化DJ-1 特发性PD？如果是这样，对DJ-1的氧化损害是否有助于偶发PD的发病机理与DJ-1基因突变相似，导致家族性PD？这些问题的答案不仅会促进我们对DJ-1在神经元生理学中的正常功能的了解，但也应产生新颖对DJ-1突变导致神经变性的分子机制的见解。完成拟议的项目应提高我们对PD发病机理的理解，并加速努力发现用于PD和相关神经退行性疾病的治疗疗法。