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

项目概要：项目1 Tau在原发性神经退行性Tau蛋白病如额颞叶痴呆（FTD， 也称为FTLD-tau）和继发性tau蛋白病如阿尔茨海默病（AD）。突变和变体 在MAPT和其他遗传位点中的突变促进了这种积累。出于必要，许多团体都专注于一个 tau代谢途径的方面，如与分子伴侣或自噬的相互作用 清除，或单一突变，如P301 L tau。这些类型的专注追求产生了 对tau生物学的许多见解但尚未导致对tau代谢的全面理解， 无论是正常还是疾病。该中心的目标是提供对tau蛋白的全面评估 代谢，包括野生型和突变型tau，以及包括其他遗传因素的影响。 修饰语在拟议的FTD无墙中心的背景下，该项目将解决 tau代谢和稳态的更多上游方面：从tau与分子的相互作用 分子伴侣来实现tau降解。FTD无墙中心的长期目标是 （CWOW）是为了充分了解tau的代谢以及它如何随着疾病突变而变化， 变体。该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， 3）个体对tau蛋白水解的效率 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酶都是MAPT和其他遗传学上的潜在节点。 突变可导致在神经变性疾病中发现的异常tau稳态。的 这项工作的基本原理是，通过系统研究tau代谢如何随着基因的变化而变化， 变异和疾病，人们可以更好地理解分子扰动诱发 tau蛋白病这样的理解将为理解蛋白质提供一个概念框架 在神经变性领域的代谢，并可能导致更好的策略，以改善tau蛋白 用于治疗和/或预防FTLD-tau和AD的清除。目标1：生成一个 了解tau、分子伴侣和共伴侣相互作用的后果。目标二： 确定PTM对tau靶向蛋白酶体和自噬/溶酶体的功能作用 系统.目的3：测试tau通路变体对tau的溶酶体蛋白水解的功能作用。 与其他项目和核心一起，该项目将评估tau代谢中的上游节点。 通路它将有助于基因变异的功能表型及其对tau代谢的影响 帮助建立由FTD CWOW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).