The Hsp90 cochaperone FKBP51 regulates tau structure and function

Hsp90 辅助伴侣 FKBP51 调节 tau 结构和功能

• 批准号: 8086376
• 负责人: Chad A. Dickey
• 金额: $ 31.79万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8086376
• 关键词: Affect; Age; Alternative Splicing; Alzheimer' s Disease; Atomic Force Microscopy; Binding; Biology; Brain; Calcium; Cells; Clinical Trials; Cognitive deficits; Complex; Disease; Enzymes; Event; Excision; Family; Gene Deletion; Genes; Goals; Heart; Heat-Shock Proteins 90; Human; In Vitro; Individual; Injection of therapeutic agent; Kinetics; Lead; Link; Microtubules; Modeling; Molecular Chaperones; Mus; NMR Spectroscopy; Neurodegenerative Disorders; Neurons; Nuclear Magnetic Resonance; Parkinson Disease; Pathogenesis; Pathology; Peptidylprolyl Isomerase; Pharmaceutical Preparations; Phenotype; Phosphorylation; Post-Translational Protein Processing; Process; Prosencephalon; Protein Binding; Protein Family; Proteins; Reaction; Recycling; Regulation; Role; Signal Transduction; Small Interfering RNA; Structure; System; Tacrolimus Binding Proteins; Tauopathies; Transgenic Mice; Variant; Work; adeno-associated viral vector; base; brain tissue; combat; drug development; genetic manipulation; improved; interest; light scattering; mouse model; mutant; new therapeutic target; novel; prevent; small hairpin RNA; sound; tau Proteins; tau aggregation; tau expression; tau mutation; therapeutic development; therapeutic target; three dimensional structure

DESCRIPTION (provided by applicant): The Hsp90-associated enzyme-FK506 binding protein 51 (FKBP51)-was recently found to co-localize with tau in neurons and physically interact with the microtubule (MT)-associated protein tau in brain tissue from humans who died from Alzheimer's disease (AD). More recently, protein levels of FKBP51 were shown to increase in forebrain neurons with age, further supporting a novel role for FKBP51 in tau processing. The goal of this study is to determine how FKBP51 regulates the biology of tau and whether it is a rational therapeutic target for treating AD, Parkinson's disease (PD), and other tauopathies. Tau aggregation is a central component of Alzheimer's disease (AD) and ~15 other neurodegenerative diseases termed tauopathies. It is now clear that the individual components of the chaperone system exist in an intricate signaling network that can exert pleiotropic effects on tau, facilitating either its degradation or stabilization. Therefore, we endeavored to identify new ways to specifically regulate individual components of the chaperone family that may be targets for therapeutic development. The Hsp90 cochaperone, FKBP51, which possesses both an Hsp90 interacting tetratricopeptide (TPR) domain and a cis-trans peptidyl-prolyl cis-trans isomerase (PPIase) domain, was found to prevent tau clearance and regulate its phosphorylation status. Regulation of the latter is dependent on the PPIase activity of FKBP51. Hsp90 enhances the association of tau with FKBP51, and clearance of tau facilitated by FKBP51 knockdown is dependent on Hsp90 variants. In vitro, FKBP51 stabilizes microtubules with tau in a reaction dependent on FKBP51 PPIase activity. Based on these new findings we propose the following aims to determine the role of FKBP51 in tau biology and pathogenesis. We will 1) investigate how FKBP51 regulates the structural ensembles and aggregation kinetics of tau, 2) determine whether FKBP51 utilizes discreet Hsp90 variants to regulate distinct tau species, and 3) determine whether genetic manipulation of FKBP51 in the brain alters tau-based pathologies and phenotypes in a transgenic mouse model of tauopathy. PUBLIC HEALTH RELEVANCE: The tau protein accumulates in more than 15 neurodegenerative diseases collectively termed "tauopathies", the most common being Alzheimer's disease. Despite this fact, only one drug is currently in clinical trials that targets the tau protein. This is largely due to our lack of understanding of how the brain deals with tau under normal circumstances. Here, we have identified a novel protein that interacts with tau and may represent a novel therapeutic target to treat Alzheimer's disease. This protein, FKBP51, can promote tau removal through a very interesting mechanism, and we will explore whether manipulation of this protein can clear tau protein from the brain. These studies may lead to drug development that can provide sufferers of tauopathies a way to combat their condition, with the ultimate goal being a cure.

描述(申请人提供)：Hsp90相关酶-FK506结合蛋白51(FKBP51)-最近被发现与tau在神经元中共定位，并在物理上与死于阿尔茨海默病(AD)的人类脑组织中的微管(MT)相关蛋白tau相互作用。最近，前脑神经元中FKBP51的蛋白水平随着年龄的增长而增加，进一步支持了FKBP51在tau加工中的一个新角色。本研究的目的是确定FKBP51如何调节tau的生物学，以及它是否是治疗AD、帕金森病(PD)和其他tau病的合理治疗靶点。Tau聚集是阿尔茨海默病(AD)和其他15种称为tauopathy的神经退行性疾病的中心组成部分。现在很清楚，伴侣系统的各个组成部分存在于一个复杂的信号网络中，该网络可以对tau发挥多效性作用，促进其降解或稳定。因此，我们努力寻找新的方法来具体调控可能成为治疗开发目标的伴侣家族的个别组成部分。Hsp90辅伴侣FKBP51既具有Hsp90相互作用的四肽(TPR)结构域，又具有顺式-反式多肽-脯氨酰顺式-反式异构酶(PPIase)结构域，可阻止tau清除并调节其磷酸化状态。后者的调节依赖于FKBP51的PPIase活性。HSP90增强了tau与FKBP51的结合，而FKBP51基因敲除促进tau的清除依赖于Hsp90变体。在体外，FKBP51在依赖于FKBP51 PPIase活性的反应中与tau稳定微管。基于这些新的发现，我们提出了以下目的，以确定FKBP51在tau生物学和发病机制中的作用。我们将1)研究FKBP51如何调节tau的结构集合和聚集动力学，2)确定FKBP51是否利用离散的Hsp90变体来调节不同的tau物种，以及3)确定在转基因tau病小鼠模型中，FKBP51在大脑中的遗传操作是否改变了基于tau的病理和表型。 公共卫生相关性：tau蛋白在15种以上的神经退行性疾病中积聚，这些疾病统称为tauopathies，最常见的是阿尔茨海默病。尽管如此，目前只有一种药物处于针对tau蛋白的临床试验中。这在很大程度上是因为我们缺乏对正常情况下大脑如何处理tau的理解。在这里，我们已经确定了一种新的蛋白质，它与tau相互作用，可能代表着治疗阿尔茨海默病的新靶点。这种名为FKBP51的蛋白质可以通过一种非常有趣的机制促进tau的去除，我们将探索操纵这一蛋白质是否可以从大脑中清除tau蛋白。这些研究可能会导致药物开发，为肌萎缩侧索硬化症患者提供一种抗击疾病的方法，最终目标是治愈。