Biology of Parkin and Its Role in Parkinson's Disease

帕金生物学及其在帕金森病中的作用

• 批准号: 8540519
• 负责人: Ted M. Dawson
• 金额: $ 12.15万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8540519
• 关键词: ABL1 gene; Accounting; Animal Model; Autopsy; Biology; Brain; Centers of Research Excellence; Data; Evaluation; Failure; Generations; Genetic; Human; In Vitro; Instruction; Knock-out; Lead; Mediating; Modeling; Modification; Molecular; Mutation; Neurodegenerative Disorders; Oxidative Stress; Parkin gene; Parkinson Disease; Pathogenesis; Patients; Phosphorylation; Phosphotransferases; Physiological; Play; Post-Translational Protein Processing; Principal Investigator; Process; Protein Tyrosine Kinase; Receptor Protein-Tyrosine Kinases; Role; Stress; Substantia nigra structure; Testing; Therapeutic; Toxic effect; Transgenic Mice; Tyrosine Phosphorylation; Ubiquitin-Proteasomal Pathway; Ubiquitination; alpha synuclein; c-abl Proto-Oncogenes; cell killing; disease-causing mutation; dopaminergic neuron; in vivo; in vivo Model; insight; loss of function mutation; neurorestoration; new therapeutic target; nitrosative stress; novel; novel therapeutics; overexpression; parkin gene/protein; prevent; receptor; research study; synucleinopathy; ubiquitin-protein ligase

Project 1: Biology of Parkin and Its Role in Parkinson's Disease Mutations in the parkin gene play a prominent role in Parkinson's disease (PD) as mutations in parkin are the main genetic cause of autosomal recessive PD and mutations in parkin also appear to play a role in familial PD. Parkin plays a pivotal role in the ubiquitin proteasomal pathway (UPP) by functioning as an ubiquitin E3 ligase. Most disease causing mutations of parkin are thought to be loss of function mutations that ultimately lead to the absence of ubiquitination and the subsequent failure of UPP-mediated degradation of parkin substrates. Thus, the abnormal accumulation of parkin substrates could play a role in the demise of substantia nigra dopaminergic neurons in patients with parkin mutations. Moreover, inactivation of parkin through dopaminergic and oxidative and nitrosative stress may play a role in sporadic PD. The stress activated non-receptor tyrosine kinase c-Abl phosphorylates and inactivates parkin and may play a critical role in sporadic PD by inactivating parkin. We propose to characterize the role of c-Abl mediated inactivation of parkin and its relationship to oxidative and nitrosative stress in sporadic PD as well as the role of parkin substrates in the pathogenesis of PD. Understanding the function and role of c-Abl and oxidative/nitrosative stress mediated inactivation of parkin may provide novel therapeutics targets to prevent the toxic effects of parkin deficiency in the degenerative process of PD. RELEVANCE (See instructions): Parkinson Disease (PD) is common neurodegenerative disease with no proven neuroprotective or neurorestorative therapy. Understanding the molecular mechanisms by which parkin inactivation leads to PD may provide novel therapeutic opportunities to maintain parkin in a catalytically active neuroprotective state.

项目1：帕金生物学及其在帕金森氏病中的作用 帕金基因的突变在帕金森氏病（PD）中起着重要作用，因为帕金的突变是 常染色体隐性PD和帕金突变的主要遗传原因似乎在家族中起作用 PD。帕金通过用作泛素E3在泛素蛋白酶体途径（UPP）中起关键作用 连接酶。人们认为大多数引起帕金突变的疾病是功能突变的丧失 导致缺乏泛素化以及随后UPP介导的帕金降解的失败 基材。因此，帕金底物的异常积累可能在消亡中发挥作用 帕克蛋白突变患者的黑质尼格拉多巴胺能神经元。而且，帕金失活 通过多巴胺能，氧化和亚硝化应激可能在零星的PD中起作用。压力 活化的非受体酪氨酸激酶C-ABL磷酸化并灭活parkin，并可能发挥关键 通过使Parkin失活在零星PD中的作用。我们建议表征C-ABL介导的失活的作用 Parkin及其与零星PD的氧化和硝化应激的关系以及Parkin的角色 PD发病机理中的底物。了解C-ABL和氧化/硝化作用的功能和作用 帕金的压力介导的失活可能会提供新的治疗靶标，以防止 帕金缺乏在PD的退化过程中。 相关性（请参阅说明）： 帕金森氏病（PD）是常见的神经退行性疾病，没有证实的神经保护或 神经训练疗法。了解帕金灭活导致的分子机制 PD可能会提供新的治疗机会，以维持帕金在催化活性的神经保护作用中 状态。