Identification of phosphorylation sites in PHF-TAU from patients with Guam amyotrophic lateral sclerosis/parkinsonism-dementia complex.
Identification of phosphorylation sites in PHF-TAU from patients with Guam amyotrophic lateral sclerosis/parkinsonism-dementia complex.
复制标题
关岛肌萎缩侧索硬化症/帕金森病-痴呆症患者 PHF-TAU 磷酸化位点的鉴定。
DOI：
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发表时间：
1996
影响因子：
3.2
通讯作者：
J. Trojanowski
中科院分区：
文献类型：
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作者：
M. Mawal;M. Schmidt;Brian J. Balin;Daniel P. Perl;V. Lee;J. Trojanowski
关岛肌萎缩侧索硬化症/帕金森病-痴呆复合体(Guam ALS/PDC)是一种进行性神经退行性疾病，其特征是由聚集的成对螺旋细丝(PHF)组成的丰富的神经原纤维缠结(NFT)。这些异常的微丝类似于经典阿尔茨海默病(AD)神经纤维病变中的PHF，最近的研究表明，Guam ALS/PDC中的tau被异常磷酸化，并且在生化上类似于经典AD中的异常tau蛋白(PHFtau)。然而，与AD中的PHFtau不同的是，关于关岛ALS/PDC中PHFtau的磷酸化特定位点的信息很少。因此，为了解决这一重要问题，我们使用13种抗体对富含缠结的关岛ALS/PDC和AD脑进行了研究，其中13种抗体定义了分布在整个AD PHFtau中的磷酸依赖或非依赖表位。这些研究确定了关岛ALS/PDC中7个先前未知的PHFtau磷酸化位点(即Thr181、Thr231、Ser262、Ser396、Ser404、Ser422，以及由单抗AT10定义的位点)，所有这些位点都在AD PHFtau中发现。事实上，蛋白质印迹、光学和免疫电子显微镜数据表明，关岛ALS/PDC中的NFTs、PHF和PHFtau与经典AD中的对应物非常相似。因此，深入了解导致关岛ALS/PDC中神经纤维病变堆积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。
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.