Parkin mediated Neural Dysfunction in Drosophila

Parkin 介导的果蝇神经功能障碍

• 批准号: 6740229
• 负责人: Leo J Pallanck
• 金额: $ 21.99万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-01 至 2005-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6740229
• 关键词: Drosophilidae; Lewy body; Parkinson' s disease; alpha synuclein; arthropod genetics; disease /disorder model; enzyme activity; enzyme induction /repression; gene mutation; gene targeting; ligase; model design /development; protein protein interaction; ubiquitin

DESCRIPTION (Provided by Applicant): Parkinson's disease is a prevalent neurodegenerative disorder characterized by tremors, rigidity, and bradykinesia. These symptoms are thought to arise from the degeneration of dopaminergic neurons in the substantia nigra pars compacta. Recently, mutations of the parkin gene, which encodes a ubiquitin-protein ligase, were found to underlie a familial form of Parkinson's disease known as autosomal recessive juvenile Parkinson's disease (AR-JP). While this advance provides clues to the mechanism responsible for pathology in AR-JP, the cellular targets of the parkin ubiquitin-protein ligase activity and the specific biochemical pathways affected by parkin mutations remain largely unknown. To address these issues, the objectives of this proposal are to create a Drosophila melanogaster model of AR-JP through mutational analysis of a Drosophila parkin ortholog, and to use this fly AR-JP model to investigate the molecular mechanisms of neuronal dysfunction underlying parkin deficiency. Two main hypotheses will be explored in this proposal: (a) parkin sequesters alpha-synuclein protein into Lewy bodies and this function represents a cellular mechanism of alpha-synuclein detoxification; (b) neurodegeneration triggered by parkin mutations results from accumulation of parkin substrate(s). To accomplish the objectives of this proposal, the following specific aims will be pursued: (1) Generate and characterize Drosophila parkin (D-parkin) mutants; (2) Determine whether altered D-parkin expression affects the time course and extent of alpha-synuclein induced neurodegeneration and Lewy body formation; (3) Identify modifiers of a D-parkin mutant phenotype; (4) Isolate D-parkin-binding components and investigate structure-function relationships in D-parkin. Results from this work should clarify the relationship between parkin dysfunction and neurodegeneration, and possibly reveal strategies for treatment of Parkinson's disease.

描述（由申请人提供）：帕金森病是一种流行病 神经退行性疾病，特征为震颤、僵硬和 运动迟缓。这些症状被认为是由退化引起的 黑质致密部的多巴胺能神经元。最近突变 编码泛素蛋白连接酶的parkin基因被发现 是一种称为常染色体隐性遗传的帕金森氏病家族形式的基础 青少年帕金森病（AR-JP）。虽然这一进展提供了线索 负责 AR-JP 病理学的机制，AR-JP 的细胞靶标 Parkin泛素蛋白连接酶活性及具体生化途径 受parkin突变的影响仍然很大程度上未知。为了解决这些问题， 该提案的目标是创建果蝇模型 通过果蝇parkin直向同源物的突变分析来鉴定AR-JP，并 使用该果蝇 AR-JP 模型来研究神经元的分子机制 Parkin 缺乏导致的功能障碍。将探讨两个主要假设 在该提案中：（a）parkin 将 α-突触核蛋白隔离到 Lewy 中 体，该功能代表 α-突触核蛋白的细胞机制 排毒； (b) Parkin突变引发的神经变性结果 来自 Parkin 底物的积累。为了实现本次活动的目标 提案，将追求以下具体目标：（1）生成和 表征果蝇 Parkin (D-parkin) 突变体； (2) 判断是否 D-parkin 表达的改变会影响 D-parkin 表达的时间进程和程度 α-突触核蛋白诱导神经变性和路易体形成； (3) 识别 D-parkin突变体表型的修饰剂； (4) 分离 D-parkin 结合 成分并研究 D-parkin 中的结构-功能关系。 这项工作的结果应该阐明 Parkin 之间的关系 功能障碍和神经退行性变，并可能揭示治疗策略 帕金森病。

项目成果

The PINK1/Parkin pathway regulates mitochondrial morphology.

PINK1/Parkin 通路调节线粒体形态。

• 发表时间: 2008-02-05
• 影响因子: 11.1
• 作者: Poole, Angela C;Thomas, Ruth E;Andrews, Laurie A;McBride, Heidi M;Whitworth, Alexander J;Pallanck, Leo J
• 通讯作者: Pallanck, Leo J

Induction of the phase II detoxification pathway suppresses neuron loss in Drosophila models of Parkinson's disease.

II 期解毒途径的诱导可抑制帕金森病果蝇模型中的神经元损失。

• 发表时间: 2008-01-09
• 作者: Trinh, Kien;Moore, Katherine;Wes, Paul D;Muchowski, Paul J;Dey, Joyoti;Andrews, Laurie;Pallanck, Leo J
• 通讯作者: Pallanck, Leo J

Genetic and genomic studies of Drosophila parkin mutants implicate oxidative stress and innate immune responses in pathogenesis.

果蝇 Parkin 突变体的遗传和基因组研究表明氧化应激和先天免疫反应在发病机制中的作用。

• 发表时间: 2005-03-15
• 影响因子: 3.5
• 作者: Greene, Jessica C;Whitworth, Alexander J;Andrews, Laurie A;Parker, Tracey J;Pallanck, Leo J
• 通讯作者: Pallanck, Leo J

Increased glutathione S-transferase activity rescues dopaminergic neuron loss in a Drosophila model of Parkinson's disease.

谷胱甘肽 S-转移酶活性的增加可挽救帕金森病果蝇模型中的多巴胺能神经元损失。

• 发表时间: 2005-05-31
• 影响因子: 11.1
• 作者: Whitworth, Alexander J;Theodore, Dorothy A;Greene, Jessica C;Benes, Helen;Wes, Paul D;Pallanck, Leo J
• 通讯作者: Pallanck, Leo J