The role of Cdc4/Fbw7 in Parkinson's Disease

Cdc4/Fbw7 在帕金森病中的作用

基本信息

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
项目类别：
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

项目摘要

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。尽管这些神经元的死亡原因尚不清楚，但帕金森病的遗传形式提供了线索。常染色体隐性青少年帕金森症 (AR-JP) 中最常见的突变基因是 PARK2，它编码 Parkin。 Parkin 缺失小鼠在其一生中不会患帕金森病，但它们的大脑显示线粒体和抗氧化功能缺陷。这一观察结果和其他观察结果表明，人类帕金森病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。我们对 SCFCdc4/Fbw7 的研究表明，这种蛋白质泛素连接酶与 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，它以 Cdc4/Fbw7（SCFCdc4/Fbw7 的限速成分）为目标，进行泛素介导的破坏。目前的提案探讨了parkin突变神经元中Cdc4/Fbw7的稳定性与parkin突变相关的表型之间的潜在联系，特别是在SCFCdc4/Fbw7底物（转录共激活剂PGC-1）的背景下。 PGC-1 控制大脑中的线粒体和抗氧化功能，因此 Parkin 突变大脑中 SCFCdc4 依赖性 PGC-1 下调可能解释了大多数（如果不是全部）已知的 Parkin 无效表型。公众健康相关性：帕金森病和相关综合征构成了一系列破坏性的神经退行性疾病。大多数遗传性帕金森病的特征是 PARK2 基因突变。目前的提案旨在确定 PARK2 基因编码的 Parkin 的功能，以期开发治疗帕金森病的新方法。