Genetic Modifiers of Protein Interaction Networks in Tauopathy

这项提案的目的是确定ApoE多态性如何改变综合性的基因表达。 蛋白质复合物的地图和子网络，这些蛋白质复合物是功能障碍的核心参与者， 阿尔茨海默病（Alzheimer's Disease，AD）我们将利用量化网络的新兴力量 Emili实验室的蛋白质组学与邻近分析相结合， 表征在tau蛋白病的经典疾病模型中发生的主要蛋白质组装。 Wolozin实验室的发现将推动这项研究， 蛋白质相互作用的动态网络驱动着tau蛋白的生物学， 病程。将通过交叉参考关键网络成员， 大型遗传学和基因组学数据集，重点关注AD风险，神经病理学结果 和人脑表达数据，以使得能够对表现出 与疾病相关的基因间相互作用这些先进的相互作用体筛选技术 是唯一适合于无偏询问疾病相关的蛋白质网络中， 个脑袋我们假设tau蛋白和RNA结合蛋白相互作用组表现出进行性的 tau蛋白病随着疾病进展而演变，并且相互作用体的结构是 由AD的遗传风险因素改变。目的1将确定APOE等位基因如何修饰 神经元相互作用体与疾病进展。我们将PS19 P301 S tau小鼠与小鼠杂交， 携带人源化ApoE 3或ApoE 4，并比较蛋白-蛋白相互作用网络， tau蛋白和RNA结合蛋白TIA 1（与病理性tau蛋白相互作用）和G3 BP （其不与病理性tau相互作用）。目的2将确定APOE等位基因 改变对传播的病理性tau的反应。我们将比较 不同的tau蛋白株改变了与病理性tau蛋白相互作用的蛋白质， 特异性ApoE同种型的表达改变了tau蛋白增殖的模式和 产生的tau相互作用体。目标3将确定如何减少关键蛋白质相互作用物 改变AD相关网络和tau蛋白病的疾病进展。这项工作将审查 减少关键网络组件如何修改相关的交互式网络， 正常疾病条件下PS19 xApoE 3或E4小鼠的疾病进展 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.