Integrative Multi-Omic Discovery of Proximal Mechanisms Driving Age-Dependent Neurodegeneration

阿尔茨海默病是最常见的神经退行性疾病，其临床特征是 认知功能障碍和病理上的细胞外淀粉样斑块和神经元内 聚集的tau沉积到神经元缠结中。虽然这种疾病的罕见形式是由 常染色体显性基因的高度外显突变，更常见形式的 疾病仍然不完全了解。深入了解导致损失的基本机制 衰老过程中神经元完整性的研究将为致力于确定 阿尔茨海默病和相关疾病中的神经变性通路。因此，为了提供一个 全面了解高等真核生物大脑退化的机制，我们将采取 在果蝇中，正向遗传学的力量以不偏不倚的方式概述了机制， 控制老化过程中神经元功能的保存。然后，将我们的发现与人类疾病联系起来 我们将使用系统生物学方法，直接整合来自eQTL分析和RNA的网络， 来自独特的高质量激光捕获患者颞神经元资源的测序数据 老年痴呆症患者和年龄和性别匹配的无神经系统疾病的对照组患者。 我们将通过进行综合代谢组学， 与阿尔茨海默病相关的果蝇模型中的磷酸蛋白质组学分析，即人tau蛋白和 转基因动物。由此产生的网络，包括以前未发现的或隐藏的节点，将被 在tau蛋白的良好表征模型中测试它们与果蝇神经变性的因果关系 和黄芪神经毒性。因此，我们的研究将在基因组规模上发现新的驱动机制， 神经变性，并将提供这些机制的普查最有可能在细胞死亡的基础上， 阿尔茨海默病及相关疾病。我们发现的基因和途径可以在 在适当的哺乳动物模型中的机制细节。

Alzheimer's disease is the most common neurodegenerative disorder and is characterized clinically by cognitive dysfunction and pathologically by the formation of extracellular amyloid plaques and intraneuronal deposition of aggregated tau into neurofibrillary tangles. Although rare forms of the disorder are caused by highly penetrant mutations in autosomal dominant genes, the pathogenesis of more common forms of the disease remains incompletely understood. A thorough understanding of the basic mechanisms driving loss of neuronal integrity during aging would provide a crucial underpinning for efforts focused on identifying the pathways mediating neurodegeneration in Alzheimer's disease and related disorders. Thus, to provide a comprehensive knowledge of mechanisms driving brain degeneration in higher eukaryotes we will take advantage of the power of forward genetics in Drosophila to outline, in an unbiased fashion, mechanisms controlling preservation of neuronal function during aging. Then, to relate our findings to human disease directly we will integrate, using a systems biology approach, networks derived from eQTL analysis and RNA sequencing data from a unique and high-quality resource of laser captured temporal neurons from patients with Alzheimer's disease and carefully age- and sex-matched control patients without neurological disease. We will further discover pathways relevant to disease by performing an integrated metabolomics and phosphoproteomic analysis in Drosophila models relevant to Alzheimer's disease, namely human tau and Aß transgenic animals. The resulting networks, including previously undiscovered, or hidden, nodes will be tested for their causal relationship to neurodegeneration in Drosophila in well-characterized models of tau and Aß neurotoxicity. Our studies will thus discover on a genome scale novel mechanisms driving neurodegeneration and will provide a census of those mechanisms most likely to underlie cell death in Alzheimer's disease and related disorders. The genes and pathways we discover can then be examined in mechanistic detail in the appropriate mammalian models.