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：帕金的生物学及其在帕金森病中的作用 parkin基因的突变在帕金森病（PD）中起着重要作用，因为parkin基因的突变是帕金森病（PD）的主要遗传因素。 常染色体隐性PD的主要遗传原因和帕金突变似乎也在家族性PD中发挥作用。 警局Parkin作为泛素E3在泛素蛋白酶体途径（UPP）中起着关键作用 连接酶大多数引起帕金突变的疾病被认为是功能突变的丧失， 导致泛素化的缺失和随后UPP介导的parkin降解的失败 印刷受体.因此，帕金底物的异常积累可能在细胞死亡中发挥作用。 帕金森突变患者的黑质多巴胺能神经元。此外，parkin的失活 通过多巴胺能和氧化和亚硝化应激可能在散发性PD中发挥作用。应力 激活的非受体酪氨酸激酶c-Abl磷酸化并使parkin失活， 通过使parkin失活而在散发性PD中发挥作用。我们建议，c-Abl介导的失活作用的特点， parkin及其与散发性PD中氧化和亚硝化应激的关系以及parkin的作用 基质在PD发病机制中的作用。了解c-Abl和氧化/亚硝化的功能和作用 应激介导的parkin失活可能提供新的治疗靶点， 帕金森病的退行性过程中parkin缺乏。 相关性（参见说明）： 帕金森病（PD）是一种常见的神经退行性疾病， 神经修复疗法了解parkin失活导致 PD可能提供新的治疗机会，以维持帕金在催化活性的神经保护作用。 状态