PATHOBIOLOGY OF NEURODEGENERATIVE DISEASES LINKED TO TAU GENE MUTATIONS

阿尔茨海默病（AD）和其他神经退行性疾病包括皮克病、进行性核上性麻痹（PSP）、皮质基底节变性（CBD）和额颞叶痴呆（FTD）的一些病例的组织病理学特征在于大脑神经元和胶质中的内含物。 内含物由微管相关蛋白tau组成。 与正常脑tau（其是能够促进微管蛋白聚合以形成微管（MT）并稳定MT的可溶性蛋白质）相反，内含物中的tau呈丝状形式。 涉及tau聚合物形成的机制仍有待阐明。最近的遗传学研究将tau突变与许多FTD与帕金森综合征（FTDP-17）联系起来，作为tau病的原因。 已经鉴定了几个错义突变（例如G272 V、N279 K、P301 L、V337 M和R406 W）和编码第二串联重复的外显子10的5个剪接位点中的突变。 后一种突变导致四个与三个重复tau的比率增加。 目前尚不清楚突变tau的存在或四个和三个重复tau比例异常的存在是否足以使神经元和/或神经胶质形成tau内含物。 此外，目前还不清楚tau蛋白的功能是否受到这些突变的损害，不同的突变是否具有不同的影响，或者这些突变是否改变了神经元对变性的易感性。 为了研究这些问题，重点是FTDP-17中鉴定的突变体，（ii）确定突变型和野生型tau在聚合潜力、对蛋白水解的敏感性和其他物理化学性质方面是否不同，（iii）研究培养细胞的反应和tau基因的突变以及项目3和4产生的转基因动物中的tau，和（v）研究转基因动物的神经元和神经胶质培养物，并确定来自具有突变型tau的小鼠的细胞是否与野生型tau的那些细胞在响应（a）微管去稳定剂秋水仙碱、（B）磷酸酶抑制剂和（c）氧化剂应激时不同。

Alzheimer's disease (AD) and other neurodegenerative disorders including Pick's disease, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and some cases of frontal temporal dementia (FTD) are characterized histopathologically by inclusions in cerebral neurons and glia. The inclusions consists of microtubule associated protein, tau. In contrast to normal brain tau, which is a soluble protein capable of promoting the polymerization of tubu7lin to form microtubules (MT) and of stabilization of MT, tau in inclusions is in filamentous form. The mechanism(s) involved in formation of tau polymers remains to be elucidated. Recent genetic studies have linked tau mutations to a number of FTD with parkinsonism (FTDP-17) as the cause of taopathy. Several missence mutations (e.g. G272V, N279K, P301L, V337M and R406W) and mutations in the 5 splice site of exon 10, which encodes the second tandem repeat, have been identified. The latter mutations result in an increase of the ratio of four to three repeat tau. Whether the presence of mutant tau or the presence of an abnormal proportion of four and three repeat tau us sufficient for neuron and/or glia to form tau inclusion remains unclear at present. Moreover, it remains unclear if the function of tau is compromised by these mutations, iv various mutations have different effects, or if these mutations alter the susceptibility of neurons to degeneration. To examine these issues focusing on mutants identified in FTDP-17, (ii0 determine if mutant and wild type tau differ in polymerization potential, susceptibility to proteolysis and other physico-chemical properties, (iii) study the response of cultured cells and mutation in tau gene as well as tau in transgenic animals generated by Projects 3 and 4, and (v) study neuronal and glial cultures of transgenic animals and determine if cells from mice with mutant tau differ from those will wild type tau in response to (a) microtubule destabilizing agent colchicine, (b) phosphatase inhibitors, and (c) oxidant stress.