Tau Conformation in Tauopathies and Neuronal Function

Tau病理是包括阿尔茨海默病在内的tau病的一个显著特征。 (AD)和阿尔茨海默病相关痴呆(ADRDS)，即进行性核上性瘫痪(PSP)， 皮质基底膜退行性变(CBD)、匹克氏病(Pick‘s病)、额颞叶痴呆(FTD)和慢性 创伤性脑病(CTE)。有些疾病是由tau基因突变引起的，但正常tau基因是病理性的。 在AD或CTE中。每种节育症都有一种疾病特有的表型、组织学表现、形态和 临床表现，但均表现为tau蛋白过度磷酸化和错误折叠。这表明了一个共同的 致病机制。我们的中心假设是tau的致病形式代表了a的错误调节。 Tau作为定位和调控微管蛋白激酶支架的正常生物学功能 和磷酸酶。我们在tau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的增加的激酶 牛顿疗法中的活动。包含磷酸酶激活结构域(PAD)的17个氨基酸的暴露是 通常受限，但在病理形式的tau中成为组成部分。Pad在所有文件中显示异常 迄今为止研究过的tau的病理形式是患者来源tau毒性的组成部分。 集合体。最近的研究表明，特定的tau磷酸化可以在空间和时间上调节pAD。 暴露，tau与PP1和GSK3b相互作用。不同的tau病的病理性tau在结构上是 不同的毒性，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，后 翻译修饰和突变。我们将描述tau在正常大脑中的生理作用。 以及AD和ADRD。我们将对tau的正常和病理功能进行分析，以检验该假说。 该tau蛋白作为一种支架，将特定的激酶和磷酸酶定位并调节到微管中。 目的1研究tau蛋白在轴索区PP1和GSK3b正常调节中的作用。我们 认为PAD的呈现仅限于正常神经元中特定的亚细胞室和 在病态下放松管制。正常和正常的tau的大量翻译后修饰(PTM) 患病的大脑提示tau功能中的一个角色，目标2将确定特定的 PTMS。我们认为病理性tau的毒性可能受疾病特异性的tau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 不同拼接形式的tau蛋白在影响PAD等呈现中的生理意义 Tau中具有生物活性的模体。最后，目标4将评估tau基因突变如何导致差异。 衬垫和其他图案的曝光。Tau异构体和PTM的发育调控可能起关键作用 AD和ADRDS在神经元发育和发病机制中的作用。PAD的规范呈现是 对于神经元功能很重要，而聚集、PTM和突变扰乱了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.