Mapping protein interactome of TREM2 and its variants to probe the etiology of Alzheimer's Disease

项目概要 骨髓细胞 2 上表达的触发受体 (TREM2) 最近成为一种主要的受体 免疫信号中枢对于维持小胶质细胞对 AD 病理的反应至关重要，以及 使小胶质细胞转变为疾病相关小胶质细胞（DAM）状态。稀有型号 R47H TREM2 中的 R62H 和 R62H 显着增加晚发性阿尔茨海默病 (AD) 的风险， 表明 TREM2 信号传导的改变足以驱动 AD 病理。 尽管令人兴奋的遗传学研究将 TREM2 变异与 AD 病因联系起来，但分子 这种基因型-表型关系的机制仅得到部分解释。 蛋白质-蛋白质相互作用 (PPI) 对于细胞信号传导和正常运作至关重要 经常观察到监管过程和 PPI 正常模式的破坏 与人类遗传疾病有关。因此，将与 TREM2 相互作用的蛋白质映射到 全系统水平是理解 TREM2 通路分子机制的基础 并剖析 AD 相关 TREM2 变体中改变的特定小胶质细胞信号传导。在 在此应用中，我们建议使用 TurboID 绘制小胶质细胞中的 TREM2 蛋白相互作用组图 - 基于邻近标记方法（目标 1），并分析 TREM2 相互作用组的变化 由 AD 相关变异 R47H 和 R62H 引起（目标 2）。完成后，我们的研究将 识别 TREM2 信号传导的新型调节因子，并深入了解 TREM2 信号传导的因果机制 AD 中的 TREM2 变体。该项目产生的知识也将有助于设计新颖的 针对 TREM2 治疗 AD 的治疗策略。

Project summary Triggering receptor expressed on myeloid cells 2 (TREM2) recently emerged as a major immune signaling hub that is essential to sustain the microglial response to AD pathology, and enable microglial transition to a disease-associated microglia (DAM) status. Rare variants R47H and R62H in TREM2 significantly increase risks for late-onset Alzheimer’s disease (AD), indicating altered TREM2 signaling is sufficient to drive AD pathology. Despite the exciting genetic studies linking TREM2 variants to AD etiology, the molecular mechanisms underlying this genotype-phenotype relationship are only partially explained. Protein-protein interactions (PPIs) are central to the proper functioning of cellular signaling and regulatory processes, and disruptions of the normal patterns of PPIs are often observed and implicated in human genetic diseases. As such, mapping proteins that interact with TREM2 on a system-wide level is fundamental for understanding molecular machinery of TREM2 pathway and dissecting specific microglial signaling that is altered in AD-associated TREM2 variants. In this application, We propose to map TREM2 protein interactome in microglia use TurboID- based proximity labeling approach (Aim 1), and to profile the change of TREM2 interactome caused by AD-associated variations R47H and R62H (Aim 2). Upon completion, our study will identify novel regulators of TREM2 signaling, and bring insights into the causal mechanisms of TREM2 variants in AD. Knowledge generated from this project will also help design novel therapeutic strategies targeting TREM2 for the treatment of AD.