Genetic Modifiers of Protein Interaction Networks in Tauopathy

这项建议的目标是确定ApoE基因的多态是如何改变全面的 蛋白质复合体的图谱和子网络，它们是功能障碍的核心参与者 发生阿尔茨海默病(AD)。我们将利用量化网络的新兴力量 埃米利实验室的蛋白质组学与邻近图谱相结合，系统地 描述在典型的直肠肌萎缩症疾病模型中出现的主要蛋白质集合。 这项研究将由沃洛津实验室的发现推动 一个动态的蛋白质相互作用网络驱动tau生物学并随着 病程。这项工作将通过交叉参考关键网络成员来进一步了解 到关注AD风险、神经病理结果的大型遗传学和基因组学数据集 和人类大脑表达数据，以实现网络成员的优先顺序显示 疾病相关的基因与基因的相互作用。这些先进的互动组筛选技术 独一无二地适用于对疾病相关蛋白质网络的无偏见询问 大脑。我们假设tau和rna结合蛋白相互作用表现出一种进行性。 在共济失调中，随着疾病的进展而演变，而且交互作用的结构是 被阿尔茨海默病的遗传危险因素修饰。目标1将确定载脂蛋白E等位基因如何修改 神经元相互作用与疾病进展。我们将PS19 P301S tau小鼠与小鼠杂交 携带人源化ApoE3或ApoE4，并比较蛋白质-蛋白质相互作用网络 Tau和RNA结合蛋白TIA1(与病理性Tau相互作用)和G3BP (它不与病理性tau相互作用)。目标2将确定载脂蛋白E等位基因如何 修改对传播的病理性tau的反应。我们将比较如何传播 不同的tau菌株改变了与病理性tau相互作用的蛋白质，以及如何 特定的载脂蛋白E亚型的表达改变了tau的传播模式和tau的性质 由此产生的tau相互作用。目标3将确定如何减少关键蛋白质相互作用因子 改变AD相关的网络，以及紧张症的疾病进展。这项工作将检验 减少关键网络组件如何修改相关的互动网络和 PS19xApoE3或E4小鼠在正常疾病条件下的疾病进展 由tau繁殖引起的进展或加速进展。

The goal of this proposal is to determine how ApoE polymorphisms modify comprehensive maps and subnetworks of protein complexes that are central players in the dysfunction occurring Alzheimer’s disease (AD). We will use the emerging power of quantitative network proteomics in the Emili laboratory combined with proximity profiling to systematically characterize the major protein assemblies that occur in a classic disease model of tauopathy. This research will be propelled by discoveries from the Wolozin laboratory demonstrating that a dynamic network of protein interactions drives tau biology and changes with the course of disease. The work will be further informed by cross-referencing key network members to large genetics and genomics datasets focused on AD risk, neuropathological outcomes and human brain expression data to enable prioritization of network members exhibiting disease-linked gene-gene interactions. These advanced interactome screening technologies are uniquely suited for unbiased interrogations of disease-related protein networks in the brain. We hypothesize that tau and RNA binding protein interactomes exhibit a progressive evolution with disease progression in tauopathy, and that the structure of the interactomes is modified by genetic risk factors for AD. Aim 1 will determine how APOE alleles modify neuronal interactomes with disease progression. We will cross PS19 P301S tau mice with mice carrying humanized ApoE3 or ApoE4, and compare protein-protein interaction networks for tau and the RNA binding proteins TIA1 (which interacts with pathological tau) and G3BP (which does not interact with pathological tau). Aim 2 will determine how APOE alleles modify responses to propagated pathological tau. We will compare how propagation of different tau strains changes the proteins that interact with pathological tau, and how expression of specific ApoE isoforms modify the pattern of tau propagation and the nature of the resulting tau interactomes. Aim 3 will determine how reduction of key protein interactors modifies AD-related networks, and disease progression in tauopathy. This work will examine the how reducing key network components modifies related interactome networks and disease progression in PS19xApoE3 or E4 mice under conditions of normal disease progression or accelerated progression induced by tau propagation.