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

项目1：Tau代谢：分子伴侣、靶向和蛋白水解

• 批准号: 10493227
• 负责人: Aimee Kao
• 金额: $ 46.41万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-27 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10493227
• 关键词: Address; Affect; Alzheimer' s Disease; Amino Acid Sequence; Animal Model; Autophagocytosis; Biology; Cells; Complex; Coupling; DNA Sequence Alteration; Databases; Degradation Pathway; Disease; Experimental Models; Focus Groups; Frontotemporal Dementia; Frontotemporal Lobar Degenerations; Gene Mutation; Genetic; Goals; Half-Life; Homeostasis; Individual; Induced pluripotent stem cell derived neurons; Lead; Lysosomes; Maps; Measures; Metabolic; Metabolic Pathway; Metabolism; Modeling; Molecular; Molecular Chaperones; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neurons; Other Genetics; Pathway interactions; Peptide Hydrolases; Phenotype; Post-Translational Modification Site; Post-Translational Protein Processing; Prevention; Proteolysis; Regulation; Research Personnel; Resolution; Resources; Signal Transduction; Site; Structure; System; TSC1 gene; Tauopathies; Testing; Variant; Work; base; cell type; genetic variant; genomic locus; improved; insight; multicatalytic endopeptidase complex; polygenic risk score; protein degradation; protein metabolism; protein protein interaction; proteostasis; tau Proteins; tau aggregation; tau interaction; tau mutation; tau phosphorylation

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).

项目摘要：项目1 tau积聚在原发性神经退行性tauopathies中，例如额颞痴呆（FTD， 还有ftld-tau）和诸如阿尔茨海默氏病（AD）等继发性tauopathies。突变和变体 在MAPT和其他遗传学地，促进了这一积累。有必要，许多小组专注于一个 TAU代谢途径的方面，例如与分子伴侣或自噬的相互作用 清除率或单个突变，例如p301l tau。这些类型的集中追求已经产生 许多对tau生物学的见解，但尚未导致对tau代谢的全面理解， 正常和疾病。该中心的目标是对tau进行全面评估 代谢，包括野生型和突变体tau，以及其他遗传的影响 修饰符。在拟议的FTD中心的情况下，该项目将解决 TAU代谢和稳态的更多上游方面：来自Tau与分子的相互作用 伴侣以实现tau降解。这个无墙的FTD中心的长期目标 （CWOW）是充分了解tau的代谢及其如何随疾病突​​变和 变体。该项目的总体目的是评估TAU代谢法规的三个节点：1） 与分子伴侣和副酮的相互作用，2）翻译后修饰的影响 蛋白质体和溶酶体靶向和3）tau蛋白水解的效率（PTM） 溶酶体蛋白酶。该项目的中心假设是分子伴侣，蛋白质体和 溶酶体靶向和溶酶体蛋白酶都是潜在的节点 突变会导致神经退行性疾病中发现的异常tau稳态。 这项工作的理由是，通过系统研究TAU代谢如何随基因的变化而变化 变体和疾病，人们可以更好地理解分子扰动 tauopathy。这种理解将为理解蛋白质提供概念框架 神经退行性领域的代谢，并可能导致更好的策略改善tau 清除FTLD-TAU和AD的治疗和/或预防。目标1：生成机械 了解Tau，分子伴侣和伴侣相互作用的后果。目标2： 确定PTM对靶向蛋白酶体和自噬/溶酶体的tau的功能效应 系统。 AIM 3：测试TAU途径变体对Tau溶酶体蛋白水解的功能效应。 与另一个项目和核心一起，该项目将评估tau代谢中的上游节点 路径。它将有助于基因变异的功能表型及其对TAU代谢的影响 为了建立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）。