The role of Cdc4/Fbw7 in Parkinson's Disease

Cdc4/Fbw7 在帕金森病中的作用

• 批准号: 8054203
• 负责人: Steven I Reed
• 金额: $ 37.22万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8054203
• 关键词: Accounting; Antioxidants; Autosomal Recesssive Juvenile Parkinsonism; Binding; Biology; Brain; Cause of Death; Cell Proliferation; Cessation of life; Cultured Cells; Data; Defect; Development; Disease; Disease Progression; Down-Regulation; F-Box Proteins; Family; Functional disorder; Genes; Health; Human; Inherited; Investigation; Juvenile Parkinson Disease; Knockout Mice; Lead; Link; Longevity; Malignant - descriptor; Mediating; Mitochondria; Modeling; Mus; Mutate; Mutation; Neurodegenerative Disorders; Neurons; Oxidative Stress; PARK2 gene; Parkinson Disease; Pathology; Phenotype; Protein Isoforms; Proteins; Proteomics; Regulation; Role; Syndrome; Testing; Transcription Coactivator; Ubiquitin; Ubiquitin-Protein Ligase Complexes; Work; base; coping; dopaminergic neuron; improved; insight; knock-down; novel therapeutic intervention; parkin gene/protein; research study; response; ubiquitin ligase; ubiquitin-protein ligase

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.

描述（由申请人提供）：帕金森氏病（PD）是一种与多巴胺能神经元选择性和进行性死亡有关的神经退行性疾病。尽管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。常染色体隐性少年帕金森氏症（AR-JP）中最常见的基因是park2，它编码帕金。 Parkin-null小鼠在其寿命中不会发育PD，但是它们的大脑在线粒体和抗氧化剂功能中表现出缺陷。这一观察结果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而无法应对氧化应激的结果。我们使用SCFCDC4/FBW7的工作提出了这种蛋白 - 泛素连接酶和帕金酶之间的功能联系。初步数据表明，帕金本身是泛素连接酶，靶向cdc4/fbw7，即cdc4/fbw7的限制成分，用于泛素介导的破坏。当前的提案探讨了parkin突变神经元中Cdc4/FBW7的稳定性与帕克蛋白突变相关的表型之间的潜在联系，尤其是在SCFCDC4/FBW7底物的背景下，转录共激活剂PGC-1。 PGC-1控制大脑中的线粒体和抗氧化功能，因此，帕金蛋白突变的大脑中的SCFCDC4依赖性PGC-1下调可以解释大多数（如果不是所有已知的Parkin-null表型）。公共卫生相关性：帕金森氏病和相关综合症构成了一组毁灭性的神经退行性疾病。帕金森氏病大多数的特征是Park2基因中的突变。当前的提案旨在确定由PARK2基因编码的Parkin的功能，以期为帕金森氏病开发新的治疗方法。