Tau Conformation in Tauopathies and Neuronal Function

Tau病理学是包括阿尔茨海默病在内的称为Tau病的疾病的突出特征 (AD)和阿尔茨海默病相关痴呆（ADRD），即进行性核上性麻痹（PSP）， 皮质基底变性（CBD）、皮克病（PiD）、额颞叶痴呆（FTD）和慢性 创伤性脑病（CTE）。有些疾病是由于tau蛋白的突变，但正常的tau蛋白是病理性的 AD或CTE。每种tau蛋白病具有疾病特异性表型、组织学表现、形态学和免疫学特征。 临床表现，但都表现出过度磷酸化和tau的错误折叠。这表明， 致病机理我们的中心假设是，tau蛋白的致病形式代表了一种 tau蛋白作为微管激酶定位和调节支架的正常生物学功能 和磷酸酶。我们在tau蛋白中发现了一个激活蛋白磷酸酶1的生物活性基序 (PP1)和糖原合成酶激酶3b（GSK3b）可能反映了一个共同的分子基础， Tau病的活动。包含磷酸酶活化结构域（PAD）的17个氨基酸的暴露是 通常是限制性的，但在病理形式的tau中变成组成性的。PAD异常显示在所有 迄今为止检查的病理形式的tau，并且是患者来源的tau的tau毒性的组分 集料.最近的研究表明，特定的tau蛋白磷酸化可以在空间和时间上调节PAD 暴露和tau与PP1和GSK3b相互作用。不同tau蛋白病中的病理性tau蛋白在结构上是 不同的，并表现出不同程度的毒性。这些变化可能反映了tau亚型的差异， 翻译修饰和突变。我们将描述tau蛋白在正常大脑中的生理作用， 以及AD和ADRD。将分析tau蛋白的正常和病理功能以检验假设 tau蛋白作为一个支架，用于定位和调节微管的特异性激酶和磷酸酶。 目的1将表征tau在轴突域中PP 1和GSK 3b的正常调节中的作用。我们 提出PAD仅限于正常神经元中的特定亚细胞区室， 在病理状态下解除管制。在正常人和正常人中，tau蛋白的许多翻译后修饰（PTM） 患病的大脑表明tau蛋白功能的作用，Aim 2将确定特定的功能后果。 PTM。我们认为病理性tau蛋白的毒性可能受到疾病特异性tau蛋白模式的调节 影响tau构象的PTM、剪接异构体和突变。目标3中的实验将确定 不同的tau剪接形式在影响PAD和其他疾病的表现中的生理意义 生物活性基序。最后，目标4将评估tau蛋白突变如何导致差异化的 暴露PAD和其他图案。tau亚型和PTM的发育调控可能起关键作用 在AD和ADRD的神经元发育和发病机制中的作用。PAD的规范介绍是 对于神经元功能重要，而聚集、PTM和突变破坏PAD的正常调节。

Tau pathology is a prominent feature of the diseases known as tauopathies including Alzheimer’s disease (AD) and Alzheimer’s Disease Related Dementias (ADRDs), i.e. Progressive Supranuclear Palsy (PSP), Cortical Basal Degeneration (CBD), Pick’s disease (PiD), Frontotemporal Dementia (FTD) and Chronic Traumatic Encephalopathy (CTE). Some diseases are due to mutations in tau, but normal tau is pathological in AD or CTE. Each tauopathy has a disease specific phenotype, histological presentation, morphology and clinical presentation, but all exhibit hyperphosphorylation and misfolding of tau. This suggests a common pathogenic mechanism. Our central hypothesis is that pathogenic forms of tau represent misregulation of a normal biological function for tau as a scaffold for localization and regulation of microtubule-based kinases and phosphatases. Our discovery of a biologically active motif in tau that activates protein phosphatase 1 (PP1) and glycogen synthase kinase 3b (GSK3b) may reflect a common molecular basis for increased kinase activities in tauopathies. Exposure of 17 amino acids comprising a Phosphatase Activation Domain (PAD) is normally restricted, but becomes constitutive in pathological forms of tau. PAD is aberrantly displayed in all pathological forms of tau examined to date and is a component of tau toxicity of patient-derived tau aggregates. Recent studies show that specific tau phosphorylations can spatially and temporally regulate PAD exposure and that tau interacts with PP1 and GSK3b. Pathological tau in different tauopathies is structurally distinct and exhibit variable degrees of toxicity. These variations may reflect differences in tau isoforms, post- translational modifications, and mutations. We will characterize the physiological roles of tau in normal brain as well as AD and ADRDs. Normal and pathological functions of tau will be analyzed to test the hypothesis that tau serves as a scaffold for localizing and regulating specific kinases and phosphatases to microtubules. Aim 1 will characterize the role of tau in normal regulation of PP1 and GSK3b in axonal domains. We propose that presentation of PAD is restricted to specific subcellular compartments in normal neurons and deregulated in pathological states. Numerous posttranslational modifications (PTMs) of tau in normal and diseased brains suggest a role in tau function and Aim 2 will identify functional consequences of specific PTMs. We propose that toxicity of pathological tau may be modulated by disease specific patterns of tau PTMs, splice isoforms and mutations that affect tau conformation. Experiments in Aim 3 will determine the physiological significance of different splice forms of tau in affecting presentation of PAD and other biologically active motifs in tau. Finally, Aim 4 will evaluate how mutations in tau may lead to differential exposure of PAD and other motifs. Developmental regulation of tau isoforms and PTMs may play critical roles in both neuronal development and pathogenesis in AD and ADRDs. Regulated presentation of PAD is important for neuronal function, while aggregation, PTMs and mutations disrupt normal regulation of PAD.