Tau Conformation in Tauopathies and Neuronal Function

描述（由申请人提供）：tau病理是多种神经系统疾病的一个突出特征，统称为tau病。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号染色体相关的帕金森病额颞叶痴呆。其中一些疾病是遗传性的，与tau基因的突变有关，但正常的tau也可能是病理性的。尽管每种tau病都有疾病特定的表型、组织学表现、形态学和神经学表现，但它们都与tau蛋白错误折叠和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。首先是构象特异性tau抗体的鉴定，这些抗体可以识别一些，但不是所有的病理形式的tau，这表明tau病中的构象多样性。其次，我们最近在tau氨基端发现了一个生物活性基序，该基序激活了一个涉及蛋白磷酸酶1 （PP1）和糖原合成酶激酶3b （GSK3b）的信号通路：17个氨基酸组成了一个磷酸酶激活结构域（PAD），为tau病中激酶活性的改变提供了分子基础。该应用的中心假设是，致病形式的tau代表了tau作为微管激酶和磷酸酶定位和调节支架的正常生物学功能的失调。该PAD区域在迄今为止所检查的所有病理形式的tau中都异常显示，并且是至少两种形式的tau毒性的必要组成部分：抑制快速轴突运输和培养中的细胞毒性。我们认为在不同的tau病中，tau的病理形式在结构上是不同的，并且具有不同程度的毒性。实验在这个应用程序将表征构象的tau从不同的

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.