Tau Metabolism in FTD: From Gene Mutations to Molecular Chaperones and Lysosomal Proteases

项目概要 病理性 tau 沉积发生在一部分神经退行性疾病中，包括额颞叶 伴有 tau 蛋白包涵体的脑叶变性（FTLD-tau）。关于 FTLD-tau 的大部分已知信息均源自 来自突变 tau 模型或过度表达。然而，对整体 tau 代谢的统一看法——从其 初始生产、与分子伴侣的相互作用、翻译后修饰、靶向 据我们所知，溶酶体/自噬以及由此产生的降解尚未产生 拟议的 FTD 无墙中心 (CWOW) 的长期目标是提高我们对 FTD-tau 的病理生物学机制。其总体目标是阐明基因， 调节 tau 代谢并确定疾病影响的分子和途径 相关的突变和变体。我们的中心假设是适当的 tau 代谢需要 分子伴侣、辅助伴侣、PTM 和降解的精确、协调作用 每个代表监管节点的机器。 tau 蛋白和其他通路成员的基因突变 可以扰乱 tau 代谢，导致 tau 积累、分泌和神经退行性变。中心 将由 Aimee Kao 博士领导，她还将领导核心 A：管理和数据核心（与共同领导的 Dr. Aimee Kao）。 Yokoyama）和项目 1：Tau 分子伴侣、靶向和蛋白水解（与 Co-I Agard 博士一起）。 David Agard 博士将负责核心 B：大分子和细胞结构核心。詹妮弗博士 横山将领导核心 C：基因组学和转录组学。最后，Celeste Karch 博士将领导该项目 2：Tau 半衰期和分泌。我们将通过四个具体目标来实现这些目标。目标 1： 了解 tau 代谢的正常过程是监管部门做出的一系列决策 节点。目标 2：识别并测试 MAPT 和其他 tau 基因变异的功能相关性 代谢基因，在体外、细胞和 iNeuron 模型中，对每个 tau 代谢调节 节点。目标 3：整合项目和核心的发现以产生 Tau 代谢和变体 数据库 (TMVdb)，将作为该字段的参考点。目标 4：整合调查结果 产生 Tau 多基因风险评分 (TPRS) 的项目和核心，该评分将对 Tau 多基因风险评分进行分层 tau蛋白病。成功完成这些目标后，拟议的 FTD CWOW 将提供 有关 tau 代谢的基本信息，确定易患 tau 蛋白病的机制节点 并生成了 TMVdb 和 TPRS，这是 tau 蛋白病和神经退行性疾病领域的新资源 研究。它将生成有关 tau 稳态的极其重要的信息和基础 以此为基础建立和框架后续对 tau 蛋白病理学和毒性的研究。

PROJECT SUMMARY Pathological tau deposition occurs in a subset of neurodegenerative disorders including frontotemporal lobar degeneration with tau inclusions (FTLD-tau). Much of what is known about FTLD-tau is derived from mutant tau models or overexpression. However, a unified view of overall tau metabolism—from its initial production, interactions with molecular chaperones, post-translational modifications, targeting to lysosomes/autophagy, and resultant degradation, to our knowledge has not been generated The long- term goal of this proposed FTD Center without Walls (CWOW) is to improve our understanding of the pathobiological mechanisms underlying FTD-tau. Its overall objective is to elucidate the genes, molecules and pathways that regulate tau metabolism and to determine the impact of disease- associated mutations and variants. Our central hypothesis is that proper tau metabolism requires the precise, coordinated action of molecular chaperones, co-chaperones, PTMs and degradation machinery that each represent regulatory nodes. Genetic mutations in tau and other pathway members can disrupt tau metabolism, leading to tau accumulation, secretion and neurodegeneration. The Center will be led by Dr. Aimee Kao, who will also lead Core A: Administration and Data Core (with Co-lead Dr. Yokoyama) and Project 1: Tau Molecular Chaperones, targeting and proteolysis (with Co-I Dr. Agard). Dr. David Agard will oversee Core B: Macromolecular and Cellular Structure Core. Dr. Jennifer Yokoyama will lead Core C: Genomics and Transcriptomics. Finally, Dr. Celeste Karch will lead Project 2: Tau Half Life and Secretion. We will achieve these objectives through four Specific Aims. Aim 1: Understand the normal process of tau metabolism as a series of decisions that are made at regulatory nodes. Aim 2: Identify and test the functional relevance of genetic variants in MAPT and other tau metabolism genes, in in vitro, cell and iNeuron models, on each of the tau metabolism regulatory nodes. Aim 3: Integrate findings from Projects and Cores to produce a Tau Metabolism and Variant Database (TMVdb), that will serve as a reference point for the field. Aim 4: Integrate findings from Projects and Cores to produce a Tau Polygenic Risk Score (TPRS), which will stratify genetic risk for tauopathy. Upon successful completion of these Aims, the proposed FTD CWOW will have provided fundamental information about tau metabolism, defined mechanistic nodes predisposing to tauopathy and generated the TMVdb and TPRS, new resources for the fields of tauopathy and neurodegeneration research. It will generate critically important information about tau homeostasis and a foundational basis from which to build and frame subsequent investigations into tau pathobiology and toxicity.