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的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，但遗传性PD形式提供了线索。常染色体隐性遗传性青少年帕金森综合征（AR-JP）中最常见的突变基因是PARK 2，它编码parkin。帕金森基因敲除小鼠在其寿命期间不会发生PD，但它们的大脑显示出线粒体和抗氧化功能的缺陷。这一和其他观察结果导致了这样的建议，即人类PD中多巴胺能神经元的死亡是由于线粒体和抗氧化剂功能障碍导致无法科普氧化应激的结果。我们对SCFCdc 4/Fbw 7的研究表明，这种蛋白质-泛素连接酶和parkin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，靶向Cdc 4/Fbw 7，SCFCdc 4/Fbw 7的限速组分，用于泛素介导的破坏。目前的建议探讨了在parkin突变的神经元中Cdc 4/Fbw 7的稳定性与parkin突变相关的表型之间的潜在联系，特别是在SCFCdc 4/Fbw 7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，因此帕金森突变大脑中SCFCdc 4依赖性PGC-1下调可以解释大多数（如果不是全部）已知的帕金森无效表型。公共卫生相关性：帕金森病和相关综合征构成了一组破坏性神经退行性疾病。大多数遗传性帕金森病的特征是PARK 2基因突变。目前的提案旨在确定由PARK 2基因编码的parkin的功能，希望开发帕金森病的新治疗方法。

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.