The role of Cdc4/Fbw7 in Parkinson's Disease

描述(申请人提供)：帕金森病(PD)是一种神经退行性疾病，与多巴胺能神经元的选择性和进行性死亡有关。尽管这些神经元的死亡原因尚不清楚，但遗传形式的帕金森病已经提供了线索。常染色体隐性遗传性青少年帕金森综合征(AR-JP)最常见的突变基因是PARK2，它编码parkin。Parkin基因缺失的小鼠在其一生中不会患上帕金森病，但它们的大脑显示出线粒体和抗氧化功能的缺陷。这一点和其他观察结果导致了这样的假设，即人类帕金森氏症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的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，它针对SCFCDc4/Fbw7的限速成分CDC4/Fbw7，进行泛素介导的破坏。目前的建议探索了parkin突变神经元中CDc4/Fbw7的稳定与parkin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，因此依赖于SCFCDC4的PGC-1在parkin突变的大脑中下调可能解释了已知的parkin缺失的大部分表型。公共卫生相关性：帕金森氏症和相关症状构成了一系列毁灭性的神经退行性疾病。大多数遗传性帕金森病的特点是PARK2基因突变。目前的提案试图确定由PARK2基因编码的parkin的功能，希望开发出治疗帕金森病的新方法。

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.