Role of PP2A in tauopathies

描述（由申请人提供）： 过度磷酸化的tau蛋白的丝状沉积物是一种主要的 许多痴呆症的病理标志，如 阿尔茨海默病（AD）和额颞叶痴呆症和帕金森症与 染色体17（FTDP-17）。蛋白磷酸酶2A的主要亚型 （PP 2A），ABaC，存在于微管（MT）细胞骨架上，结合tau， 并调节磷酸化状态和MT结合/稳定活性 细胞中的tau。拟议研究的主要目标是进一步 描述结构和功能之间的相互关系， ABaC，tau和MT，并解决其破坏促进 在所有tau蛋白病中过度磷酸化形式的tau蛋白的积累。的 第一个目标将集中于确定PP 2A/tau和PP 2A/MT的主要性质 在体外和细胞中的相互作用。它们对MT的功能意义 稳定性以及tau蛋白的分布和磷酸化， 在目标2中进行了研究。PP 2A或tau蛋白突变体的表达，以及新的 磷酸化敏感的tau抗体将用于解决相关性 PP 2A/tau/MT相互作用在选择的神经元和非神经元细胞 模型在目标3中，将通过以下方法比较ABaC和tau蛋白的分布： 非痴呆对照、AD和 其他tau蛋白病，以评估PP 2A表达水平的变化是否 与tau蛋白阳性细胞中存在过度磷酸化的tau蛋白有关 病变此外，生物化学方法将被用来关联这些 PP 2A的表达、活性和羧甲基化水平 在相同的大脑区域中决定。这些研究应该提供新的见解 PP 2A在调节tau和MT中的功能作用 细胞骨架，并在PP 2A本身的调节。阐明机制 控制正常的tau蛋白功能和调节是 了解导致tau异常的过程， 功能和AD和其他人类tau蛋白病中的神经退行性事件。

DESCRIPTION (provided by applicant): Filamentous deposits of hyperphosphorylated tau proteins are a major pathological hallmark of a large number of dementing disorders, such as Alzheimer's disease (AD) and frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17). The predominant isoform of protein phosphatase 2A (PP2A), ABaC, is present on the microtubule (MT) cytoskeleton, binds to tau, and regulates the phosphorylation state and MT binding/stabilizing activities of tau in cells. The primary goals of the proposed studies are to further characterize the structural and functional interrelationships that exist among ABaC, tau, and MTs, and address the hypothesis that their disruption promotes the accumulation of hyperphosphorylated forms of tau in all tauopathies. The first aim will focus on establishing major properties of PP2A/tau and PP2A/MT interactions in vitro and in cells. Their functional significance for MT stability and the distribution and phosphorylation of tau proteins will then be investigated in Aim 2. Expression of PP2A or tau protein mutants, and novel phosphorylation-sensitive tau antibodies will be used to address the relevance of PP2A/tau/MT interactions in chosen neuronal and non-neuronal cellular models. In Aim 3, the distribution of ABaC and tau proteins will be compared by immunohistochemistry in human brain regions from non-demented controls, AD, and other tauopathies, in order to assess whether changes in PP2A expression levels are associated with the presence of hyperphosphorylated tau in tau-positive lesions. In addition, biochemical methods will be used to correlate these results with the expression, activity and carboxymethylation levels of PP2A determined in the same brain regions. These studies should provide new insights into the functional role of PP2A in the regulation of tau and the MT cytoskeleton, and in the regulation of PP2A itself. Elucidating the mechanisms that govern normal tau functions and regulation is a key step towards understanding the processes that lead to the tau abnormalities, compromised MT functions, and neurodegenerative events in AD and other human tauopathies.