PHF TAU IN NEURODEGENERATIVE DISEASE IN MICRONESIA

与阿尔茨海默氏症类似的神经退行性疾病的患病率 帕金森病（PD）和肌萎缩侧索硬化症 (ALS)在马里亚纳群岛的查莫罗人中异常高。尽管 这些查莫罗人疾病（称为关岛ALSIPDC）和 其他地方的AD、PD或ALS，关岛ALS/PDC大脑的主要发现 与经典AD中的神经元缠结（NE;Ts）相似，存在大量神经元缠结。 例如，NFT AD和关岛ALS/PDC的主要结构要素 是成对的螺旋丝（PHF），以前的研究表明， AD和关岛ALSIPDC中的PHF是由异常的 磷酸化tau蛋白（PHFtau）。尽管如此，我们发现活检 衍生的正常成人tau蛋白在几乎所有的 先前在AD PHFtau中鉴定的位点，尽管程度较低， 活组织检查衍生的正常人tau蛋白经历快速和选择性的 在PHFtau中异常保留的位点的去磷酸化。我们 还提供了数据，表明磷酸化的差异， 正常人tau相对于PHFtau的状态可能是由于受损的 AD脑内磷酸酶活性。蛋白磷酸酶2A （PP 2A）与PHFtau未能进行有效的细胞内转录有关。 去磷酸化由于PP 2A使tau蛋白去磷酸化， PP 2A的辅助亚基、催化亚基和调节亚基可能发挥重要作用， 在PHFtau的产生中起重要作用。虽然退化的 关岛的ALSIPDC神经元几乎完全与 NFT的积累和脑脊液中的TAN水平 (CSF)AD患者的发病率相对于对照组升高， 和PHFtau积累的生物学意义 对AD和关岛ALS/PDC的神经系统病变了解甚少。 因此，项目4将测试以下假设： 神经元损伤在神经元变性中起作用， 关岛ALS/PDC。为了实现这一目标，我们将评估 CSF tan水平升高的意义，检查PP 2A在 PHFtau和缠结形成的发病机制，并表征 大脑中缠结轴承与正常神经元的分子图谱 有和没有关岛ALS/PDC的患者。这些研究将提供 PHFtau发病机制的重要见解， 关岛ALS/PDC的病变，并阐明这些病变如何导致神经元 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.