Genome-wide analysis of tau neurotoxicity

描述(申请人提供)：阿尔茨海默病是最常见的神经退行性疾病，病理特征是异常磷酸化和聚集的tau蛋白在神经元内沉积，并形成细胞外淀粉样斑块。Tau在神经纤维缠结中的异常沉积也是一组不太常见的疾病的主要病理特征，统称为tauopathies。为了确定控制tau诱导的神经退化的分子机制，我们和其他人在简单而强大的遗传模型生物果蝇中模拟了tau引起的神经变性。果蝇的遗传学、生物化学和细胞生物学实验为了解果蝇的发病机制提供了重要线索。然而，为这些研究提供基础的无偏见的前向基因筛查虽然很有价值，但到目前为止仍然不完整。在这里，我们建议使用新创建和强大的全基因组转基因RNAi收集来进行体内tau神经毒性的全面遗传分析。我们将用人类阿尔茨海默病神经元中最先进的转录组学来补充这些研究。这些研究将首次提供控制tau对有丝分裂后神经元毒性的机制的全面分析，并将确定许多新的高价值治疗靶点。我们的研究将特别重要，因为越来越多的数据来自全基因组相关研究，表明遗传对阿尔茨海默病和相关的变态反应的影响，但几乎没有明确的证据表明这些新发现的基因产物在神经退行性疾病发病机制中的作用机制。

DESCRIPTION (provided by applicant): Alzheimer's disease is the most common neurodegenerative disorder and is characterized pathologically by the intraneuronal deposition of abnormally phosphorylated and aggregated tau protein and by the formation of extracellular amyloid plaques. Abnormal deposition of tau into neurofibrillary tangles is also the primary pathologic feature of a group of less common disorders, collectively termed the "tauopathies." To define the molecular mechanisms controlling tau-induced neurodegeneration we and others have modeled tauopathies 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 tauopathies. However, the unbiased forward genetic screens providing the bases for these studies, while valuable, have to date remained incomplete. Here we propose to use newly created and powerful whole- genome transgenic RNAi collections to perform comprehensive genetic analysis of tau neurotoxicity in vivo. We will complement these studies by with a state of the art transcriptomics in human Alzheimer's disease neurons. These studies will for the first time provide a comprehensive analysis of mechanisms controlling tau toxicity to postmitotitc 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 Alzheimer's disease and related tauopathies, but with little clear evidence as to the mechanism of action of these newly identified gene products in neurodegenerative disease pathogenesis.