A systems biology approach in Drosophila to identify novel factors that influence AD pathogenicity

阿尔茨海默病(AD)是一种常见的神经退行性疾病，影响超过10%的人口 65岁以上，以及几乎50%的85岁以上的人。早发性家族性AD通常是由基因突变引起的 这是仅有的三个常染色体基因之一。相比之下，更常见的晚发型散发性AD(LOAD)，即 与淀粉样蛋白β积聚、tau过度磷酸化和线粒体功能障碍有关，似乎 受到大量基因的影响，其中大部分是未知的。全基因组关联 对全基因组上位性和基因-×-环境相互作用的研究有助于总体 风险。阿尔茨海默病的遗传基础和下游效应都是系统范围的和复杂的。来解析这个 AD的原因和后果都很复杂，在这里我们创建了一个新的系统生物学管道和 将其应用于果蝇黑腹果蝇的阿尔茨海默病强大遗传模型。有三个人 相辅相成的目标，我们的流水线使我们能够创建一个全面的AD的基因-表型图谱。我们的 First Aim使用完全测序的果蝇遗传参考小组(DGRP)来鉴定苍蝇品系， 放大或改善Aβ和tau对年龄相关性神经退行性变的影响，并表征 代谢和单细胞大脑转录网络与这种扩增和保护相关。 第二个目标是将苍蝇开发为下游系统范围表型的强大模型，从 大脑特定单细胞类型的电生理测量，用于行走的机器视觉分析 步态动力学。帮助我们了解基因和分子网络的上游变异(目标1) 翻译到下游的细胞和行为表型(Aim 2)，Aim 3检查了 Aβ和Tau，包括它们的周转、聚集和丰度以及Aβ和Tau对 线粒体的完整性，包括线粒体的形态、运输和周转。然后Aim 3将进行比较 对Aβ和tau有害影响最敏感的菌株中的这些元素与 最具抗药性，描述了影响Aβ和tau毒性的分子和细胞机制。至 为了实现这些目标，我们建设了一支互补性很强的优秀研究团队 技能。我们在这里公布的和初步的数据表明，我们有能力测量 并构建和分析与该风险相关的大规模分子网络，以 从单个神经元的电脉冲到复杂的行为，研究AD的表型后果 整只苍蝇，并发现将基因型与表型联系起来的潜在生化机制。上一首 对果蝇的研究在我们对基础生物学和疾病的理解中都发挥了重要作用 机制，包括神经退行性疾病。这里提出的研究有可能为我们带来新的 洞察影响自然人群中AD发病的复杂、相互作用的途径，潜在地 为AD的治疗干预提供了新的生物标志物和新的机会。

Alzheimer's disease (AD) is a common neurodegenerative disorder affecting more than 10% of the population over age 65, and almost 50% of those over age 85. Early onset familial AD is typically caused by mutations in one of just three autosomal genes. In contrast, the more common, late-onset sporadic AD (LOAD), which is associated with amyloid β accumulation, tau hyperphosphorylation, and mitochondrial dysfunction, appears to be influenced by a very large number of genes, most of which are unidentified. Genome-wide association studies of LOAD point to genome-wide epistasis and gene-×-environment interactions contributing to overall risk. Both the genetic basis and the downstream effects of AD are system-wide and complex. To parse this complexity in both causes and consequences of AD, here we create a novel Systems Biology Pipeline and apply it to a powerful genetic model of AD using the fruit fly, Drosophila melanogaster. With three complementary aims, our pipeline enables us to create a comprehensive genotype-phenotype map of AD. Our first aim uses the fully sequenced Drosophila Genetic Reference Panel (DGRP) to identify fly strains that amplify or ameliorate the effects of Aβ and tau on age-related neurodegeneration, and characterizes the metabolomic and single-cell brain transcriptomic networks associated with this amplification and protection. The second aim develops the fly as a powerful model for downstream systems-wide phenotypes, from electrophysiological measures of specific single cell types in the brain, to machine-vision analysis of walking gait dynamics. To help us understand how upstream variation in genes and molecular networks (Aim 1) translates to downstream cellular and behavioral phenotypes (Aim 2), Aim 3 examines the protein dynamics of Aβ and tau, including their turnover, aggregation and abundance, and the influence of Aβ and tau on mitochondrial integrity, including mitochondrial morphology, trafficking and turnover. Aim 3 will then compare these elements in strains that are most sensitive to the deleterious effects of Aβ and tau with those that are most resistant, delineating molecular and cellular mechanisms that influence Aβ and tau toxicity. To accomplish these aims, we have constructed an outstanding team of researchers with highly complementary skills. Our published and preliminary data presented here establish our ability to measure genotypic variation in AD risk in Drosophila and construct and analyze large-scale molecular networks associated with that risk, to study the phenotypic consequences of AD from electrical pulses in a single neuron to intricate behaviors in a whole fly, and to discover the underlying biochemical mechanisms that link genotype to phenotype. Previous work with Drosophila has played an important role in our understanding of both basic biology and of disease mechanism, including neurodegenerative diseases. The studies proposed here have the potential to shed new insight on the complex, interacting pathways that influence AD pathogenesis in natural populations, potentially leading to new biomarkers and new opportunities for therapeutic intervention in AD.