Biology of Parkin and Its Role in Parkinson's Disease

项目1：帕金氏生物学及其在帕金森氏病中的作用 Parkin基因的突变在帕金森氏病(PD)中起着重要作用，因为parkin基因的突变是 常染色体隐性遗传性帕金森病的主要遗传原因和Parkin基因突变似乎也在家族性帕金森病中起作用 警察。Parkin通过作为泛素E3在泛素蛋白酶体途径(UPP)中发挥关键作用 连接酶。大多数导致帕金森氏症的疾病突变被认为是最终导致功能突变的丧失 导致泛素化缺失和随后UPP介导的停车降解失败 底物。因此，帕金底物的异常堆积可能在帕金森病的死亡中发挥作用。 帕金氏突变患者的黑质多巴胺能神经元。此外，停用停车 通过多巴胺能、氧化和亚硝酸应激可能在散发性帕金森病中起作用。压力 激活的非受体酪氨酸激酶c-Abl磷酸化和失活parkin，并可能发挥关键作用 帕金森失活在散发性帕金森病中的作用。我们建议对c-abl介导的失活作用进行表征。 散发性帕金森病患者PARKIN的表达及其与氧化和亚硝化应激的关系及PARKIN的作用 帕金森病发病机制的底物。了解c-Abl和氧化/亚硝酸盐的功能和作用 应激介导的parkin失活可能提供新的治疗靶点来防止 帕金氏缺乏症在帕金森病退变过程中的作用。 相关性(请参阅说明)： 帕金森病(PD)是一种常见的神经退行性疾病，没有得到证实的神经保护或 神经恢复性疗法。了解parkin失活导致的分子机制 帕金森病可能提供新的治疗机会以维持帕金森病在催化活性神经保护中的作用 州政府。

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.