DJ-1 in Dopaminergic Neuronal Function and Survival

DJ-1 在多巴胺能神经元功能和存活中的作用

• 批准号: 6963776
• 负责人: Jie Shen
• 金额: $ 36.8万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6963776
• 关键词: Parkinson' s disease; behavior test; dopamine; electrophysiology; gene expression; gene mutation; gene targeting; genetically modified animals; high performance liquid chromatography; laboratory mouse; microdialysis; neural degeneration; neural transmission; neurogenetics; neurophysiology; oxidation; parkin gene /protein; phenotype; psychomotor function; substantia nigra

Parkinson's disease (PD) is an age-related neurodegenerative disorder characterized by resting tremor, rigidity and bradykinesia. These clinical features are thought to arise from reduced dopaminergic input to the striatum, which is caused by the degeneration of dopaminergic neurons in the substantia nigra. The occurrence of PD is largely sporadic, but clinical syndromes resembling sporadic PD can also be caused by mutations in the alpha-synuclein, parkin, DJ-I and PINK1 genes. Elucidation of the pathogenic mechanisms underlying the selective dopaminergic degeneration in familial parkinsonism will likely provide important clues to the pathogenic mechanisms responsible for idiopathic PD. The recessive inheritance mode of the mutations and the existence of large exonic deletions in the, parkin, DJ-1 and PINK1 genes indicate that loss of function of a single gene product can lead to clinical manifestations of parkinsonism and selective dopaminergic degeneration. We take advantage of the identification of these genes to study the mechanisms by which loss-of-function mutations in these genes result in manifestations of parkinsonian features through the generation of mutant mice. Our previous generation and analysis of parkin-/- mice have shown nigrostriatal deficits and mitochondrial dysfunction in the absence of loss of dopaminergic neurons, suggesting that these functional deficits likely precede neurodegeneration, and that mitochondrial dysfunction may be causal in PD pathogenesis. In this proposal, we hypothesize that loss-of function mutations in the DJ-1 gene alter the normal physiology of dopaminergic neurons in the substantia nigra, ultimately leading to their degeneration and production of parkinsonian phenotypes. To test this hypothesis, we propose the following three Specific Aims. First, we will generate and analyze DJ-1-/-null mice for disruption of normal dopaminergic neurotransmission, loss of dopaminergic neurons and motor impairments. Second, we will determine whether loss of DJ-1 function results in mitochondrial dysfunction and increased oxidative damage. Third, since mouse models bearing mutations in a single pathogenic gene, such as parkin-null mice and alpha-synuclein transgenic mice, fail to develop the cardinal feature of PD, namely selective dopaminergic degeneration, we will investigate whether the presence of two pathogenic mutations accelerates the dysfunction and degeneration of dopaminergic neurons in mice deficient in both DJ-1 and parkin. Our long-term goal is to develop a genetic mouse model that recapitulates all central features of PD and to characterize the molecular pathways responsible for PD pathogenesis.

帕金森氏病（PD）是一种与年龄相关的神经退行性疾病，其特征是静止震颤，僵硬和头霉素。这些临床特征被认为是纹状体的多巴胺能输入降低引起的，纹状体是由黑质中多巴胺能神经元变性引起的。 PD的发生在很大程度上是零星的，但是类似于零星PD的临床综合征也可能是由α-突触核蛋白，Parkin，DJ-I和Pink1基因突变引起的。阐明家族性帕金森氏症选择性多巴胺能变性背后的致病机制可能会为导致特发性PD的致病机制提供重要的线索。突变的隐性遗传模式以及帕金，DJ-1和Pink1基因中大型外显子缺失的存在表明，单个基因产物的功能丧失可以导致帕金森主义和选择性多巴胺能退化的临床表现。我们利用这些基因的鉴定来研究这些基因中功能丧失突变的机制，从而通过产生突变小鼠导致帕金森氏症特征的表现。我们对帕克蛋白 - / - 小鼠的上一代和分析表明，在没有多巴胺能神经元丧失的情况下，骨纹状体缺陷和线粒体功能障碍，这表明这些功能性缺陷可能是神经退行性的之前的，而线粒体功能障碍可能是PD PDDEDENEGONENEN中的神经性功能障碍。在此提案中，我们假设DJ-1基因中的功能丧失突变改变了尼格拉省多巴胺能神经元的正常生理学，最终导致了它们的退化和产生帕金森氏症表型。为了检验这一假设，我们提出以下三个特定目标。首先，我们将生成和分析DJ-1 - / - 无效小鼠，以破坏正常的多巴胺能神经传递，多巴胺能神经元和运动障碍的丧失。其次，我们将确定DJ-1功能的丧失是否导致线粒体功能障碍并增加氧化损伤。 Third, since mouse models bearing mutations in a single pathogenic gene, such as parkin-null mice and alpha-synuclein transgenic mice, fail to develop the cardinal feature of PD, namely selective dopaminergic degeneration, we will investigate whether the presence of two pathogenic mutations accelerates the dysfunction and degeneration of dopaminergic neurons in mice deficient in both DJ-1 and帕金。我们的长期目标是开发一种遗传小鼠模型，该模型概括了PD的所有主要特征，并表征了负责PD发病机理的分子途径。