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: 8392290
• 负责人: Chad A. Dickey
• 金额: $ 30.67万
• 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/8392290
• 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.

描述（由申请人提供）：最近发现Hsp 90相关酶-FK 506结合蛋白51（FKBP 51）-与神经元中的tau共定位，并与死于阿尔茨海默病（AD）的人的脑组织中的微管（MT）相关蛋白tau物理相互作用。最近，FKBP 51的蛋白质水平在前脑神经元中随年龄增加而增加，进一步支持FKBP 51在tau加工中的新作用。本研究的目的是确定FKBP 51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蛋白病的合理治疗靶点。Tau聚集是阿尔茨海默病（AD）和约15种称为Tau蛋白病的其他神经退行性疾病的中心组分。现在很清楚，分子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产生多效性作用，促进其降解或稳定。因此，我们致力于确定新的方法来特异性地调节分子伴侣家族的各个组分，这些组分可能是治疗发展的靶点。Hsp 90辅伴侣蛋白FKBP 51具有Hsp 90相互作用的三肽（TPR）结构域和顺-反肽基脯氨酰顺-反异构酶（PPIase）结构域，被发现阻止tau蛋白清除并调节其磷酸化状态。后者的调节依赖于FKBP 51的PPI酶活性。Hsp 90增强tau与FKBP 51的结合，并且通过FKBP 51敲低促进的tau的清除依赖于Hsp 90变体。在体外，FKBP 51在依赖于FKBP 51 PPIase活性的反应中用tau稳定微管。基于这些新发现，我们提出以下目标，以确定FKBP 51在tau生物学和发病机制中的作用。我们将1）研究FKBP 51如何调节tau的结构集合和聚集动力学，2）确定FKBP 51是否利用离散的Hsp 90变体来调节不同的tau种类，3）确定FKBP 51在脑中的遗传操作是否改变tau蛋白病转基因小鼠模型中基于tau的病理和表型。