Tau Conformation in Tauopathies and Neuronal Function

描述（由申请人提供）：Tau病理学是统称为Tau病变的多种神经系统疾病的突出特征。这些疾病包括阿尔茨海默病（AD）、进行性核上性麻痹（PSP）、皮质基底变性（CBD）、皮克病和与17号染色体相关的额颞叶痴呆伴帕金森综合征。其中一些疾病是遗传性的，与tau基因突变有关，但正常的tau也可能是病理性的。尽管每种tau蛋白病都具有疾病特异性表型、组织学表现、形态学和神经学表现，但它们都与tau蛋白的错误折叠和tau蛋白磷酸化改变有关。这种临床多样性阻碍了对共同致病机制的研究。最近的两项发现为tau病理学提供了新的见解。第一个是鉴定构象特异性tau抗体，其识别tau的一些但不是全部病理形式，表明tau病变内的构象多样性。其次，我们最近证明了tau氨基末端的生物活性基序，其激活涉及蛋白磷酸酶1（PP 1）和糖原合成酶激酶3b（GSK 3b）的信号传导途径：包含磷酸酶激活结构域（PAD）的17个氨基酸为tau蛋白病中改变的激酶活性提供了分子基础。本申请的中心假设是tau的致病形式代表tau作为基于微管的激酶和磷酸酶的定位和调节的支架的正常生物学功能的失调。该PAD区域异常地显示在迄今为止检查的所有病理形式的tau中，并且是至少两种形式的tau毒性的必要组分：快速轴突运输的抑制和培养物中的细胞毒性。我们提出，在不同的tau蛋白病的病理形式的tau蛋白在结构上是不同的，具有不同程度的毒性。本申请中的实验将表征来自不同来源的tau的构象。 tau蛋白病，并使用真实的和合成的聚集体评价它们在影响PP 1/GSK 3b途径和轴突运输方面的相对毒性。我们进一步假设，不同的tau构象的毒性可能是由疾病特异性模式的tau磷酸化和构象调制。将确定AD、PSP和CBD的这些改变的疾病特异性模式。将分析tau蛋白的正常和病理功能，以检验tau蛋白作为定位和调节微管特异性激酶和磷酸酶的支架的假设。我们将集中在正常调节的PP 1和GSK 3b的微管丰富的轴突领域的tau的作用，并确定这些磷酸转移酶与tau的相互作用域。通过tau定位PP 1/GSK 3b通路允许对这些活动进行空间和时间控制，并且我们提出PAD的呈递仅限于正常神经元中的特定亚细胞区室，并且在病理状态下解除调节。与该模型一致，tau、PP 1和GSK 3b都与神经元发育有关。tau蛋白亚型、构象和磷酸化的发育调节在神经元发育中可能起关键作用。我们认为，PAD的调节介绍是重要的神经突起生长和轴突蛋白的靶向在正常的神经元发育和功能，使我们能够了解之间的关系，错误折叠的tau蛋白和正常的tau蛋白功能的毒性。

DESCRIPTION (provided by applicant): Taupathology is a prominent feature of multiple neurological diseases known collectively as tauopathies. These include Alzheimer's disease (AD), Progressive Supranuclear Palsy (PSP), Cortical Basal Degeneration (CBD), Pick's disease, and Frontotemporal Dementia with Parkinsonism linked to chromosome 17. Some of these diseases are hereditary, associated with mutations in the tau gene, but normal tau may also be pathological. Although each tauopathy has a disease specific phenotype, histological presentation, morphology, and neurological presentation, all of them are associated with misfolded tau and altered phosphorylation of tau. The search for a common pathogenic mechanism has been hindered by this clinical diversity. Two recent findings provide new insight into tau pathology. The first is identification of conformation specific tau antibodies that recognize some, but not all, pathological forms of tau, suggesting conformational diversity within the tauopathies. Second, our recent demonstration of a biologically active motif in the tau amino terminus that activates a signaling pathway involving protein phosphatase 1 (PP1) and glycogen synthase kinase 3b (GSK3b): 17 amino acids comprising a Phosphatase Activation Domain (PAD) provides a molecular basis for altered kinase activities in tauopathies. The central hypothesis of this application is that pathogenic forms of tau represent a misregulation of a normal biological function for tau as a scaffold for localization and regulation of microtubule based kinases and phosphatases. This PAD region is aberrantly displayed in all pathological forms of tau examined to date and is a necessary component of at least two forms of tau toxicity: inhibition of fast axonal transport and cell toxicity in culture. We propose that pathological forms of tau in different tauopathies are structurally distinct with variable degrees f toxicity. Experiments in this application will characterize the conformations of tau from different tauopathies and evaluate their relative toxicity in affecting the PP1/GSK3b pathway and axonal transport using authentic and synthetic aggregates. We further hypothesize that toxicity of different tau conformers may be modulated by disease specific patterns of tau phosphorylation and conformation. Disease specific patterns of these alterations will be determined for AD, PSP and CBD. 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. We will focus on the role of tau in the normal regulation of PP1 and GSK3b in microtubule rich domains of the axon and identify interaction domains with tau for these phosphotransferases. The localization of the PP1/GSK3b pathway by tau allows for spatial and temporal control of these activities and we propose that presentation of PAD is restricted to specific subcellular compartments in normal neurons and deregulated in pathological states. Consistent with this model, tau, PP1 and GSK3b have all been implicated in neuronal development. Developmental regulation of tau isoforms, conformation, and phosphorylation may play critical roles in neuronal development. We suggest that the regulated presentation of PAD is important for neurite outgrowth and targeting of axonal proteins during normal neuronal development and function, allowing us to understand the relationship between the toxicity of misfolded tau and normal tau function.