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

项目摘要 病理性tau蛋白沉积发生在神经退行性疾病的子集中，包括额颞叶 脑叶变性伴tau包涵体（FTLD-tau）。关于FTLD-tau的大部分已知信息都来自 突变的tau模型或过度表达。然而，整体tau代谢的统一观点-从其 初始生产，与分子伴侣的相互作用，翻译后修饰，靶向 溶酶体/自噬，以及由此产生的降解，据我们所知，还没有产生长期的- 这个拟议的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代谢的分子和途径，并确定疾病的影响- 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 每个机器代表监管节点。tau和其他通路成员的基因突变 可破坏tau代谢，导致tau积累、分泌和神经变性。中心 将由Aimee Kao博士领导，他还将领导核心A：行政和数据核心（与联合领导人Dr. Yokoyama）和项目1：Tau分子伴侣，靶向和蛋白水解（与Co-I Agard博士）。 博士大卫阿加德将监督核心B：大分子和细胞结构核心。詹妮弗 Yokoyama将领导核心C：基因组学和转录组学。最后，塞莱斯特·卡奇博士将领导该项目 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蛋白代谢的正常过程是在调控过程中做出的一系列决定， 结目的2：鉴定和测试MAPT和其他tau蛋白中遗传变异的功能相关性 在体外，细胞和iNeuron模型中，对每种tau代谢的调节 结目标3：整合项目和核心的发现，以产生Tau代谢和变体 数据库（TMVdb），该数据库将作为该领域的参考点。目标4：整合 项目和核心，以产生一个Tau多基因风险评分（TPRS），这将分层遗传风险， tau蛋白病在成功完成这些目标后，拟议的FTD CWOW将提供 关于tau代谢的基本信息，定义的易患tau病变的机制节点 并产生了TMVdb和TPRS，这是tau蛋白病和神经变性领域的新资源， research.它将产生关于tau蛋白稳态的至关重要的信息， 建立和框架随后对tau病理生物学和毒性的研究的基础。

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.