PHF TAU IN NEURODEGENERATIVE DISEASE IN MICRONESIA

类似阿尔茨海默氏症的神经退行性疾病的患病率 疾病(AD)、帕金森病(PD)和肌萎缩侧索硬化症 在马里亚纳群岛的查莫罗人中，肌萎缩侧索硬化症的发病率异常高。尽管 这些查莫罗病(称为关岛ALSIPDC)和 AD、PD或ALS在其他地方，关岛ALS/PDC脑中的主要发现 有丰富的神经原纤维缠结(NE；TS)，就像经典的AD一样。 例如，NFTs AD和关岛ALS/PDC的主要结构要素 是成对螺旋丝(PHF)，以前的研究表明 AD和关岛ALSIPDC的PHF是由异常形成的 磷酸化tau蛋白(PHFtau)。尽管如此，我们还是做了活检 衍生的正常成人tau在几乎所有的 以前在公元前PHFtau发现的地点，尽管程度较小， 活体组织来源的正常人tau经历快速和选择性 在PHFtau中异常保留的位点上的去磷酸化。我们 也提供了数据，表明磷酸化的差异 正常人类tau与PHFtau的状态可能是由于受损 阿尔茨海默病患者脑组织中的磷酸酶活性。事实上，蛋白磷酸酶2A (PP2A)被牵连到PHFtau未能有效地接受 去磷酸化。由于PP2A使tau去磷酸化，因此 PP2A的辅助、催化和调节亚基可能发挥作用 在PHFtau的产生中起着核心作用。尽管地球的退化 关岛ALSIPDC中的神经元几乎完全与 脑脊液中NFTs的蓄积和棕褐色的水平 AD患者脑脊液(CSF)较对照组升高，其发病机制 PHFtau的积累及其生物学意义 阿尔茨海默病和关岛ALS/PDC中的神经纤维损害知之甚少。 因此，项目4将测试富含PHFtau的假设 神经原纤维损伤在神经细胞退行性变中起作用 关岛ALS/PDC。为了做到这一点，我们将评估生物 脑脊液tan水平升高的意义，检测PP2A在脑脊液中的作用 PHFtau和缠结形成的发病机制，并描述了 大脑中承载缠结的神经元与正常神经元的分子图谱 患有和不患有关岛ALS/PDC的患者。这些研究将提供 对PHFtau发病机制的重要认识 关岛ALS/PDC的损害，并阐明这些损害如何导致神经元 在关岛ALS/PDC的损失。

The prevalence of neurodegenerative disorders similar to Alzheimer's disease (AD), Parkinson's disease (PD) and Amyotrophic Lateral Sclerosis (ALS) is unusually high among Chamorros in the Mariana Islands. Despite similarities between these Chamorro diseases (known as Guam ALSIPDC) and AD, PD or ALS elsewhere, the predominant findings in Guam ALS/PDC brains are abundant neurofibrillary tangles (NE;Ts) like those in classic AD. For example, the major structural elements of NFTs AD and Guam ALS/PDC are paired helical filaments (PHFs), and previous studies showed that the PHFs in AD and Guam ALSIPDC are formed from abnormally phosphorylated tau proteins (PHFtau). Although, we showed that biopsy derived normal adult human tau is phosphorylated at nearly all of the sites previously identified in AD PHFtau, albeit to a lesser extent, biopsy derived normal human tau undergoes rapid and selective dephosphorylation at sites that are abnormally retained in PHFtau. We also provided data to suggest that differences in the phosphorylation state of normal human tau versus PHFtau may be due to impaired phosphatase activity in the AD brain. Indeed, protein phosphatase 2A (PP2A) was implicated in the failure of PHFtau to undergo efficient dephosphorylation. Since PP2A dephosphorylates tau, alterations in the accessory, catalytic and regulatory subunits of PP2A could play a central role in the generation of PHFtau. Although the degeneration of neurons in Guam ALSIPDC is associated almost exclusively with the accumulation of NFTs, and the levels of tan in the cerebrospinal fluid (CSF) of AD patients are elevated relative to controls, the pathogenesis and biological significance of accumulations of PHFtau in neurofibrillary lesions in AD and Guam ALS/PDC are poorly understood. Thus, Project 4 will test the hypothesis that PHFtau-rich neurofibrillary lesions play a role in the degeneration of neurons in Guam ALS/PDC. To accomplish this, we will assess the biological significance of elevated levels of CSF tan, examine the role of PP2A in the pathogenesis of PHFtau and tangle formation, and characterize the molecular profile of tangle bearing versus normal neurons in the brains of patients with and without Guam ALS/PDC. These studies will provide important insights into the pathogenesis of PHFtau in the hallmark lesions of Guam ALS/PDC, and clarify how these lesions lead to neuron loss in Guam ALS/PDC.