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，其特点是 病理上由异常磷酸化和聚集的α-突触核蛋白在神经元内沉积 蛋白。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的病理 一组更常见的疾病的特征，称为α-突触核病症。要定义 我们和其他人模拟的控制α-突触核蛋白诱导的神经变性的分子机制 简单而强大的遗传模式生物果蝇中的α-突触核素病。遗传、生化 而果蝇的细胞生物学实验为研究果蝇的发病机制提供了重要线索。 α--突触核病症。然而，为这些研究提供基础的无偏见的前向基因筛查， 虽然有价值，但到目前为止，仍未完成。在这里，我们建议使用一个新创建的强大的 果蝇α-突触核苷酸病模型对α-突触核蛋白的全面遗传分析 体内神经毒性。这些研究将首次提供对控制机制的广泛分析。 α-突触核蛋白对有丝分裂后神经元的毒性，并应确定许多新的高价值治疗靶点。 随着越来越多的数据从全基因组关联中浮现出来，我们的研究将变得尤为重要 研究表明基因对帕金森氏症和相关的α-突触核糖核病有影响，但几乎没有 这些新发现的基因产物在神经退行性变中作用机制的明确证据 疾病发病机制。