Mawal-Dewan M, Schmidt M L, Balin B, Perl D P, Lee V M, Trojanowski J Q
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.
J Neuropathol Exp Neurol. 1996 Oct;55(10):1051-9.
Guam Amyotrophic Lateral Sclerosis/Parkinsonism-Dementia Complex (Guam ALS/PDC) is a progressive neurodegenerative disorder characterized by abundant neurofibrillary tangles (NFTs) composed of aggregated paired helical filaments (PHFs). These abnormal filaments resemble the PHFs in neurofibrillary lesions of classic Alzheimer's disease (AD), and recent studies demonstrated that tau in Guam ALS/PDC is aberrantly phosphorylated and biochemically similar to the abnormal tau proteins (PHFtau) in classic AD. However, unlike PHFtau in AD, there is little information on the specific sites of phosphorylation in PHFtau from Guam ALS/PDC. Thus, to address this important issue, we examined tangle-rich Guam ALS/PDC and AD brains by Western blot, immunoelectron microscopy and immunohistochemistry using 13 antibodies to defined phosphate-dependent or -independent epitopes distributed throughout AD PHFtau. These studies identified 7 previously unknown sites of phosphorylation in PHFtau from Guam ALS/PDC (i.e. Thr181, Thr231, Ser262, Ser396, Ser404, Ser422, and the site defined by monoclonal antibody AT10), all of which also are found in AD PHFtau. Indeed, the Western blot, light and immunoelectron microscopic data suggest that NFTs, PHFs and PHFtau in Guam ALS/PDC are very similar to their counterparts in classic AD. Thus, insights into mechanisms leading to the accumulation of neurofibrillary lesions in Guam ALS/PDC may advance understanding of the pathogenesis and biological consequences of these lesions in classic AD.
关岛肌萎缩侧索硬化症/帕金森病-痴呆综合征（Guam ALS/PDC）是一种进行性神经退行性疾病，其特征是由聚集的双螺旋丝（PHF）组成的大量神经原纤维缠结（NFT）。这些异常细丝类似于经典阿尔茨海默病（AD）神经原纤维病变中的PHF，最近的研究表明，关岛ALS/PDC中的tau蛋白异常磷酸化，并且在生化性质上与经典AD中的异常tau蛋白（PHFtau）相似。然而，与AD中的PHFtau不同，关于关岛ALS/PDC中PHFtau磷酸化的特定位点的信息很少。因此，为了解决这个重要问题，我们使用针对分布在整个AD PHFtau中的特定磷酸化依赖性或非依赖性表位的13种抗体，通过蛋白质免疫印迹、免疫电子显微镜和免疫组织化学，对富含缠结的关岛ALS/PDC和AD脑进行了检测。这些研究确定了关岛ALS/PDC中PHFtau的7个以前未知的磷酸化位点（即Thr181、Thr231、Ser262、Ser396、Ser404、Ser422以及单克隆抗体AT10所定义的位点），所有这些位点在AD PHFtau中也能找到。实际上，蛋白质免疫印迹、光学显微镜和免疫电子显微镜数据表明，关岛ALS/PDC中的NFT、PHF和PHFtau与经典AD中的非常相似。因此，深入了解导致关岛ALS/PDC中神经原纤维病变积累的机制，可能会促进对这些病变在经典AD中的发病机制和生物学后果的理解。
