Genome Wide Analysis of Alpha-Synuclein Neurotoxicity

α-突触核蛋白神经毒性的全基因组分析

• 批准号: 10021759
• 负责人: MEL B FEANY
• 金额: $ 17.9万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-25 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10021759
• 关键词: Address; Animal Model; Biochemical; Biological; Biological Models; Cells; Clinical; Cytoplasmic Inclusion; Data; Defect; Deposition; Diffuse; Disease; Drosophila genus; Equipment and supply inventories; Functional disorder; Gene Dosage; Genes; Genetic; Genetic Models; Genetic Screening; Genomics; Human; Impairment; Lewy Bodies; Lewy Body Dementia; Mediating; Modeling; Modification; Molecular; Movement Disorders; Multiple System Atrophy; Nerve Degeneration; Neurites; Neurodegenerative Disorders; Neuroglia; Neurologist; Neurons; Parkinson Disease; Parkinson' s Dementia; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Physiological; Point Mutation; Population; Process; Proteins; Somatotype; Synapses; System; Testing; Time; Toxic effect; alpha synuclein; alpha synuclein gene; base; cell type; clinically significant; design; dopaminergic neuron; early onset; experimental study; gene product; genetic analysis; genetic approach; genome wide association study; genome-wide; genome-wide analysis; in vivo; insight; nervous system disorder; neuropathology; neurotoxicity; non-motor symptom; novel; protein aggregate; synucleinopathy; therapeutic target

Parkinson's disease is the most common neurodegenerative movement disorder and is characterized pathologically by the intraneuronal deposition of abnormally phosphorylated and aggregated α-synuclein protein. Abnormal deposition of α-synuclein into neuronal and glial aggregates is also the primary pathologic feature of a group of collectively even more common disorders, termed the α-synucleinopathies. To define the molecular mechanisms controlling α-synuclein induced neurodegeneration we and others have modeled α-synucleinopathies in the simple and powerful genetic model organism Drosophila. Genetic, biochemical and cell biological experiments in Drosophila have provided important clues regarding the pathogenesis of α-synucleinopathies. However, the unbiased forward genetic screens providing the bases for these studies, while valuable, have to date remained incomplete. Here we propose to use a newly created and powerful Drosophila model of α-synucleinopathies to perform a comprehensive genetic analysis of α-synuclein neurotoxicity in vivo. These studies will for the first time provide a broad analysis of mechanisms controlling α-synuclein toxicity to postmitotic neurons and should identify many new high-value therapeutic targets. Our studies will be particularly important as more and more data emerges from genome wide associated studies showing genetic influences on Parkinson's disease and related α-synucleinopathies, but with little clear evidence as to the mechanism of action of these newly identified gene products in neurodegenerative disease pathogenesis.

帕金森氏病是最常见的神经退行性运动障碍，其特征是 绝对磷酸化和聚集的α-突触核蛋白的鼻内沉积在病理上。 蛋白质。 α-突触核蛋白在神经元和神经胶质聚集体中的异常沉积也是主要病理 一组统称更常见的疾病的特征称为α-突触核病。定义 控制α-突触核蛋白诱导神经退行性的分子机制我们和其他人已经建模 简单而强大的遗传模型生物果蝇中的α-突触核病。遗传，生化 果蝇中的细胞生物学实验提供了有关的重要线索 α-突触核疾病。但是，无偏向的前进遗传筛选为这些研究提供了基础， 虽然有价值，但必须保持不完整。在这里，我们建议使用新创建且功能强大的 α-突触核苷的果蝇模型，以对α-突触核蛋白进行全面的遗传分析 体内神经毒性。这些研究将首次对控制机制进行广泛的分析 α-突触核蛋白对有丝分裂后神经元的毒性，应识别许多新的高价值治疗靶标。 我们的研究将特别重要，因为越来越多的数据来自基因组广泛相关的 研究表明遗传对帕金森氏病和相关α-突触核的影响，但很少 关于这些新鉴定的基因产物在神经退行性中的作用机理的明确证据 疾病发病机理。