Molecular and Cellular Analysis of DJ-1 Function

DJ-1 功能的分子和细胞分析

• 批准号: 7635825
• 负责人: Asa Abeliovich
• 金额: $ 34.9万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7635825
• 关键词: Address; American; Animal Genetics; Attention; Biochemical; Brain; Cell Survival; Cell physiology; Cells; Cellular Stress Response; Clinical; Data; Dimerization; Disease; Distant; Dopamine; Elbow; Etiology; Gait; Gene Expression Profiling; Genes; Genetic; Genetic Models; Homologous Gene; Human Genetics; Inherited; Knock-out; Lead; Levodopa; Light; Link; Molecular; Molecular Chaperones; Mus; Muscle Rigidity; Mutation; Neurodegenerative Disorders; Organism; Oxidation-Reduction; Oxidative Stress; Parkinson Disease; Pathology; Peptide Hydrolases; Physiological; Play; Proteins; Recording of previous events; Resolution; Rest Tremor; Roentgen Rays; Role; Signal Transduction; Structure; Testing; Tissues; Toxic effect; Vertebrates; alpha synuclein; base; catalase; dimer; dopaminergic neuron; early onset; in vivo; mutant; neurofilament; neuroimaging; neuron development; presynaptic; protein misfolding; research study; response; stressor

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a slowly progressive but devastating neurodegenerative disorder that afflicts over 1 million Americans. The etiology of Parkinson's disease has posed a particularly challenging problem to investigate, in large part because of the lengthy disease course. Pathological studies have correlated cellular oxidative stress or protein misfolding with PD. The identification of several genes that underlie familial, inherited forms of PD has allowed for a molecular approach to PD. Recently, mutations in DJ-1 have been found to lead to autosomal recessive, early onset PD. The clinical history of DJ-1-associated familial PD is typical of the disease, including rest tremor, rigidity, gait difficulty, and responsiveness to levodopa treatment. Functional neuroimaging of the brain reveals a presynaptic dopamine deficit consistent with PD. The normal cellular function of DJ-1 is unknown, but the ubiquitous expression of DJ-1 in vertebrates and the high degree of conservation among DJ-1 homologues among diverse species suggest that DJ-1 subserves important cellular functions. DJ-1 homologues have been implicated in several biochemical and cellular roles including protease, amidotransferase, catalase, and chaperone activities, complicating the interpretation of DJ-1 function. The expression of DJ-1 and homologues is induced ii cellular stress responses, suggesting a possible link between DJ-1 mutation and PD pathology. Our preliminary data indicate that DJ-1 is a redox-dependent molecular chaperone that plays an important role in the cellular response to oxidative stress. We propose to investigate the mechanism of DJ-1 activity using complementary biochemical, cellular, and mouse genetic approaches.

描述（由申请人提供）：帕金森氏病（PD）是一种缓慢而毁灭性的神经退行性疾病，遭受了超过100万美国人的影响。帕金森氏病的病因在很大程度上提出了一个特别具有挑战性的问题，这在很大程度上是由于较长的疾病过程。病理研究与PD相关的细胞氧化应激或蛋白质折叠率错折叠。基于家族性，遗传形式的PD的几种基因的鉴定允许使用分子方法。最近，已经发现DJ-1中的突变导致常染色体隐性，早期发作PD。与DJ-1相关的家族性PD的临床病史是典型的疾病，包括休息震颤，僵化，步态难度以及对左旋多巴治疗的反应性。大脑的功能神经影像学表明与PD一致的突触前多巴胺缺陷。 DJ-1的正常细胞功能尚不清楚，但是DJ-1在脊椎动物中的无处不在表达，并且在不同物种中DJ-1同源物中的高度保护表明DJ-1子维护dj-1子维护的重要细胞功能。 DJ-1同源物已与几种生化和细胞角色有关，包括蛋白酶，酰胺转移酶，过氧化氢酶和伴侣活性，使DJ-1功能的解释变得复杂。 DJ-1和同源物的表达是诱导的II细胞应激反应，这表明DJ-1突变与PD病理学之间可能存在联系。我们的初步数据表明，DJ-1是一种依赖氧化还原的分子伴侣，在细胞对氧化应激的反应中起重要作用。我们建议使用互补的生化，细胞和小鼠遗传方法研究DJ-1活性的机制。