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病中的作用 Parkin 基因突变在帕金森病 (PD) 中发挥着重要作用，因为 Parkin 基因突变是帕金森病 (PD) 的主要致病因素。 常染色体隐性 PD 的主要遗传原因和 Parkin 突变似乎也在家族性中发挥作用 PD。 Parkin 通过作为泛素 E3 发挥作用，在泛素蛋白酶体途径 (UPP) 中发挥关键作用 连接酶。大多数引起 Parkin 疾病的突变被认为是最终导致功能丧失的突变。 导致泛素化缺失以及随后 UPP 介导的 Parkin 降解失败 基材。因此，parkin底物的异常积累可能在死亡中发挥作用。 Parkin 突变患者的黑质多巴胺能神经元。此外，帕金蛋白失活 通过多巴胺能以及氧化和亚硝化应激可能在散发性PD中发挥作用。压力 激活的非受体酪氨酸激酶 c-Abl 磷酸化并失活 Parkin，可能发挥关键作用 通过灭活 Parkin 在散发性 PD 中的作用。我们建议描述 c-Abl 介导的失活的作用 Parkin的表达及其与散发性PD氧化和亚硝化应激的关系以及parkin的作用 PD 发病机制中的底物。了解 c-Abl 和氧化/亚硝基的功能和作用 应激介导的parkin失活可能提供新的治疗靶点，以防止其毒性作用 PD 退行性过程中 Parkin 缺陷。 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，尚无经过证实的神经保护或治疗方法 神经修复疗法。了解 Parkin 失活导致的分子机制 PD 可能提供新的治疗机会，以维持 Parkin 的催化活性神经保护作用 状态。