Role of PP2A in tauopathies

描述(由申请人提供)： 过度磷酸化的tau蛋白的丝状沉积是主要的 大量痴呆症的病理特征，如 阿尔茨海默病(AD)与额颞叶痴呆和帕金森病相关 17号染色体(FTDP-17)。蛋白磷酸酶2A的主要异构体 (PP2A)，ABaC，存在于微管(MT)细胞骨架上，与tau结合， 并调节磷酸化状态和MT结合/稳定活性 细胞中的tau蛋白。拟议研究的主要目标是进一步 描述以下各项之间存在的结构和功能相互关系 ABAC、tau和MTS，并解决了它们的中断促进 过度磷酸化形式的tau在所有tau病中的积聚。这个 第一个目标将集中在建立PP2A/tau和PP2A/MT的主要性质上 体外和细胞内的相互作用。它们对MT的功能意义 然后，tau蛋白的稳定性、分布和磷酸化将被 目的2.PP2A或tau蛋白突变体的表达，以及新的 磷酸化敏感的tau抗体将被用来解决相关性 PP2A/tau/MT在选定的神经细胞和非神经细胞中的相互作用 模特们。在目标3中，Abac和tau蛋白的分布将通过以下方式进行比较 非痴呆对照组、AD和AD患者脑区的免疫组织化学研究 其他肌萎缩侧索硬化症，以评估PP2A表达水平的变化 与tau阳性的tau蛋白过度磷酸化有关 损伤。此外，还将使用生化方法来关联这些 结果与PP2A的表达、活性和羧甲基化水平有关 是在相同的大脑区域决定的。这些研究应该会提供新的见解 探讨PP2A在tau和MT调节中的作用 细胞骨架，以及对PP2A本身的调节。阐明其作用机制 管理正常的tau功能和监管是迈向 了解导致tau异常的过程，损害MT 阿尔茨海默病和其他人类肌萎缩侧索硬化症的功能和神经退行性事件。

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.