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: 8240435
• 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/8240435
• 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; public health relevance; 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（由申请人提供）：最近发现 Hsp90 相关酶 FK506 结合蛋白 51 (FKBP51) 与神经元中的 tau 蛋白共定位，并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 发生物理相互作用。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 蛋白加工中的新作用。本研究的目的是确定 FKBP51 如何调节 tau 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) 和约 15 种其他称为 tau 病的神经退行性疾病的核心组成部分。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，可以对 tau 蛋白发挥多效性作用，促进其降解或稳定。因此，我们努力寻找新的方法来特异性调节伴侣家族的各个成分，这些成分可能是治疗开发的目标。 Hsp90 辅助伴侣 FKBP51 具有 Hsp90 相互作用的四肽 (TPR) 结构域和顺反肽基脯氨酰顺反异构酶 (PPIase) 结构域，被发现可以防止 tau 清除并调节其磷酸化状态。后者的调节取决于 FKBP51 的 PPIase 活性。 Hsp90 增强 tau 与 FKBP51 的关联，FKBP51 敲低促进 tau 的清除取决于 Hsp90 变体。在体外，FKBP51 在依赖于 FKBP51 PPIase 活性的反应中用 tau 蛋白稳定微管。基于这些新发现，我们提出以下目标，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 的结构整体和聚集动力学，2) 确定 FKBP51 是否利用谨慎的 Hsp90 变体来调节不同的 tau 物种，以及 3) 确定大脑中 FKBP51 的基因操作是否会改变转基因小鼠 tau 病模型中基于 tau 的病理学和表型。 公共健康相关性：tau 蛋白在超过 15 种统称为“tau蛋白病”的神经退行性疾病中积累，其中最常见的是阿尔茨海默病。尽管如此，目前只有一种针对 tau 蛋白的药物正在进行临床试验。这很大程度上是由于我们对正常情况下大脑如何处理 tau 蛋白缺乏了解。在这里，我们发现了一种与 tau 相互作用的新蛋白质，可能代表治疗阿尔茨海默病的新治疗靶点。这种蛋白质 FKBP51 可以通过一种非常有趣的机制促进 tau 蛋白的去除，我们将探索操纵这种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tau蛋白病患者提供一种对抗疾病的方法，最终目标是治愈疾病。