The role of Cdc4/Fbw7 in Parkinson's Disease

描述（由申请人提供）：帕金森病（PD）是一种与多巴胺能神经元选择性和进行性死亡相关的神经退行性疾病。虽然这些神经元的死亡原因尚不清楚，但遗传形式的PD提供了线索。常染色体隐性遗传病（AR-JP）中最常见的突变基因是编码parkin的PARK2。帕金森氏症小鼠在其一生中不会患上帕金森氏症，但它们的大脑在线粒体和抗氧化功能方面存在缺陷。这一发现和其他观察结果表明，人类PD中多巴胺能神经元的死亡是由于线粒体和抗氧化功能障碍导致无法应对氧化应激的结果。我们对SCFCdc4/Fbw7的研究表明，这种蛋白-泛素连接酶与帕金蛋白之间存在功能联系。初步数据表明，parkin本身是一种泛素连接酶，可靶向Cdc4/Fbw7，即SCFCdc4/Fbw7的限速成分，用于泛素介导的破坏。目前的建议探讨了帕金森突变神经元中Cdc4/Fbw7的稳定与与帕金突变相关的表型之间的潜在联系，特别是在SCFCdc4/Fbw7底物，转录共激活因子PGC-1的背景下。PGC-1控制着大脑中的线粒体和抗氧化功能，因此，在帕金森突变的大脑中，scfcdc4依赖性PGC-1的下调可以解释大多数（如果不是全部的话）已知的帕金森无表型。公共卫生相关性：帕金森病和相关综合征构成了一组毁灭性的神经退行性疾病。大多数遗传性帕金森病以PARK2基因突变为特征。目前的建议旨在确定parkin的功能，由PARK2基因编码，希望开发新的治疗帕金森病的方法。

DESCRIPTION (provided by applicant): Parkinson's Disease (PD) is a neurodegenerative disorder associated with selective and progressive death of dopaminergic neurons. Although the cause of death for these neurons is not known, hereditary forms of PD have provided clues. The most frequently mutated gene in autosomal recessive juvenile Parkinsonism (AR-JP) is PARK2, which encodes parkin. Parkin-null mice do not develop PD during their lifespan, but their brains show defects in mitochondrial and antioxidant functions. This and other observations have led to the proposal that death of dopaminergic neurons in human PD is a result of inability to cope with oxidative stress due to mitochondrial and antioxidant dysfunction. Our work with SCFCdc4/Fbw7 has suggested a functional link between this protein-ubiquitin ligase and parkin. Preliminary data suggest that parkin, itself a ubiquitin ligase, targets Cdc4/Fbw7, the rate- limiting component of SCFCdc4/Fbw7, for ubiquitin-mediated destruction. The current proposal explores the potential links between stabilization of Cdc4/Fbw7 in parkin-mutated neurons and the phenotypes associated with parkin mutation, particularly in the context of an SCFCdc4/Fbw7 substrate, the transcriptional co-activator PGC-1. PGC-1 controls mitochondrial and antioxidant function in the brain, and therefore SCFCdc4-dependent PGC-1 downregulation in parkin-mutated brains could account for most if not all of the known parkin-null phenotypes. PUBLIC HEALTH RELEVANCE: Parkinson's disease and related syndromes constitute a set of devastating neurodegenerative disorders. Most inherited Parkinson's disease is characterized by mutations in the PARK2 gene. The current proposal seeks to determine the function of parkin, encoded by the PARK2 gene, in the hope of developing new therapeutic approaches to Parkinson's disease.