The Hsp90 cochaperone FKBP51 regulates tau structure and function

描述（由申请人提供）：hsp90相关酶- fk506结合蛋白51 (FKBP51)-最近被发现与神经元中的tau共定位，并与死于阿尔茨海默病（AD）的人脑组织中的微管（MT）相关蛋白tau相互作用。最近，FKBP51蛋白水平在前脑神经元中随着年龄的增长而增加，进一步支持了FKBP51在tau加工中的新作用。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种被称为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发挥多效作用，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个体成分，这些成分可能是治疗发展的目标。Hsp90合作伙伴FKBP51具有Hsp90相互作用的四肽（TPR）结构域和顺式-反式肽-脯氨酸顺式-反式异构酶（PPIase）结构域，被发现可以阻止tau清除并调节其磷酸化状态。后者的调控依赖于FKBP51的PPIase活性。Hsp90增强了tau与FKBP51的关联，FKBP51敲低促进tau的清除依赖于Hsp90变体。在体外，FKBP51在依赖于FKBP51 PPIase活性的反应中稳定tau微管。基于这些新发现，我们提出以下目标来确定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的结构集合体和聚集动力学，2)确定FKBP51是否利用离散的Hsp90变异来调节不同的tau物种，以及3)确定大脑中FKBP51的遗传操作是否会改变转基因小鼠tau病模型中基于tau的病理和表型。

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.