Genome-wide analysis of tau neurotoxicity

描述（由申请人提供）：阿尔茨海默病是最常见的神经退行性疾病，其病理特征是神经元内异常磷酸化和聚集的tau蛋白沉积以及细胞外淀粉样斑块的形成。tau蛋白在神经原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“tau病”。为了确定控制tau诱导的神经变性的分子机制，我们和其他人在简单而强大的遗传模式生物果蝇中建立了tau病模型。果蝇的遗传、生化和细胞生物学实验为研究牛头病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正向遗传筛选虽然有价值，但迄今为止仍然不完整。在这里，我们建议使用新创建的强大的全基因组转基因RNAi集合来进行体内tau神经毒性的全面遗传分析。我们将通过对人类阿尔茨海默病神经元的转录组学研究来补充这些研究。这些研究将首次全面分析控制有丝分裂后神经元的tau毒性的机制，并应确定许多新的高价值的治疗靶点。随着越来越多的全基因组相关研究数据显示遗传对阿尔茨海默病和相关的tau病变的影响，但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缺乏明确的证据，我们的研究将变得尤为重要。

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.