Project 1: Tau metabolism: molecular chaperones, targeting and proteolysis

项目总结：项目1 Tau在原发性神经退行性疾病中积聚，例如额颞叶痴呆(FTD， 也称FTLD-tau)和继发性tau病，如阿尔茨海默病(AD)。突变和变种 在MAPT和其他遗传位点促进这种积累。不可避免的是，许多团体都专注于其中一个 Tau代谢途径的一个方面，如与分子伴侣或自噬的相互作用 清除，或单个突变，如P301L tau。这些类型的专注追求产生了 对tau生物学有许多见解，但尚未导致对tau代谢的全面了解， 无论是在正常情况下还是在疾病中。该中心的目标是提供对tau的全面评估 代谢，包括野生型和突变型tau，以及包括其他基因的影响 修饰符。在拟议的无墙FTD中心的背景下，该项目将解决 Tau代谢和动态平衡的更多上游方面：来自tau与分子的相互作用 实现tau降解的伴侣。这个无墙FTD中心的长期目标是 (CWow)是完全了解tau的新陈代谢以及它如何随着疾病的突变和 变种。本项目的总体目标是评估tau代谢调节的三个节点：1) 与分子伴侣和辅助伴侣的相互作用，2)翻译后修饰的影响。 TES(PTMS)对蛋白酶体和溶酶体的靶向性和3)个体对tau蛋白的降解效率 溶酶体蛋白酶。该项目的中心假设是分子伴侣、蛋白酶体和 溶酶体靶向和溶酶体蛋白水解酶都是MAPT和其他基因的潜在节点 突变可能导致神经退行性疾病中异常的tau稳态。这个 这项工作的理论基础是通过系统研究tau新陈代谢如何随着基因的变化而变化 变种和疾病，人们可以更好地理解导致 紧张症。这样的理解将为理解蛋白质提供一个概念框架。 神经变性领域的新陈代谢，并可能导致更好的策略来改善tau 治疗和/或预防FTLD-tau和AD的许可。目标1：生成机械化的 了解tau、分子伴侣和辅助伴侣相互作用的后果。目标2： 确定PTMS对tau靶向蛋白酶体和自噬/溶酶体的功能影响 系统。目的3：检测tau途径变异体对tau溶酶体蛋白分解的功能影响。 与其他项目和核心一起，该项目将评估tau代谢的上游节点 路径。这将有助于基因变异的功能表型及其对tau代谢的影响。 协助建立FTD CWow所产生的资源，即Tau代谢途径 数据库(TMDB)和Tau多基因风险评分(TPRS)。

PROJECT SUMMARY: Project 1 Tau accumulates in primary neurodegenerative tauopathies such as frontotemporal dementia (FTD, also FTLD-tau) and secondary tauopathies such as Alzheimer’s Disease (AD). Mutations and variants in MAPT and other genetic loci promote this accumulation. By necessity, many groups focus on one aspect of the tau metabolic pathway, such as interactions with molecular chaperones or autophagic clearance, or a single mutation, such as P301L tau. These types of focused pursuits have generated many insights into tau biology but have not yet led to comprehensive understanding of tau metabolism, both normally and in disease. The \ goal of this center is to provide a comprehensive assessment of tau metabolism, inclusive of wild-type and mutant tau, as well as including effects of other genetic modifiers. Within the context of the proposed FTD Center without Walls, this project will address the more upstream aspects of tau metabolism and homeostasis: from tau interactions with molecular chaperones to achieving tau degradation. The long-term goal of this FTD Center without Walls (CWOW) is to fully understand the metabolism of tau and how it changes with disease mutations and variants. The overall objective of this project is to assess three nodes of tau metabolic regulation: 1) interactions with molecular chaperones and co-chaperones, 2) effects of post-translational modifica- tions (PTMs) on proteasomal and lysosomal targeting and 3) efficiency of tau proteolysis by individual lysosomal proteases. This project’s central hypothesis is that molecular chaperones, proteosomal and lysosomal targeting and lysosomal proteases are all potential nodes at which MAPT and other genetic mutations can contribute to the aberrant tau homeostasis found in neurodegenerative diseases. The rationale for this work is that through systematic study of how tau metabolism changes with gene variants and disease, one can better comprehend the molecular perturbations predisposing to tauopathy. Such understanding would provide a conceptual framework for understanding protein metabolism in the field of neurodegeneration and could lead to better strategies to improve tau clearance for treatment and/or prevention of FTLD-tau and AD. Aim 1: Generate a mechanistic understanding of the consequences of tau, molecular chaperone and co-chaperone interactions. Aim 2: Determine the functional effects of PTMs on tau targeting to the proteasome and autophagy/lysosome systems. Aim 3: Test the functional effects of tau pathway variants on lysosomal proteolysis of tau. Together with the other Project and Cores, this Project will assess upstream nodes in the tau metabolic pathway. It will contribute to functional phenotyping of gene variants and their effect on tau metabolism to aid in building the resources generated by the FTD CWOW, namely the Tau Metabolic Pathway Database (TMDB) and the Tau Polygenic Risk Score (TPRS).