Genome Wide Analysis of Alpha-Synuclein Neurotoxicity

帕金森病是最常见的神经退行性运动障碍， 病理上通过异常磷酸化和聚集的α-突触核蛋白的神经元内沉积 蛋白α-突触核蛋白异常沉积到神经元和神经胶质聚集体中也是原发性病理性 这是一组更常见的疾病的特征，称为α-突触核蛋白病。以限定 控制α-突触核蛋白诱导的神经退行性变的分子机制，我们和其他人已经模拟了 简单而强大的遗传模式生物果蝇中的α-突触核蛋白病。遗传的，生化的 果蝇的细胞生物学实验提供了重要的线索， α-突触核蛋白病然而，为这些研究提供基础的无偏正向遗传筛选， 虽然很有价值，但迄今仍不完整。在这里，我们建议使用一个新创建的和强大的 果蝇α-突触核蛋白病模型对α-突触核蛋白进行综合遗传分析 体内神经毒性。这些研究将首次提供一个广泛的分析机制控制 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的治疗靶点。 我们的研究将特别重要，因为越来越多的数据来自基因组范围内的相关数据， 研究显示遗传对帕金森病和相关的α-突触核蛋白病的影响，但很少 这些新发现的基因产物在神经退行性疾病中的作用机制的明确证据 发病机理

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.