美国波士顿儿童医院Judith A. Steen研究团队发现，Tau翻译后修饰图谱可确定患者的异质性和阿尔茨海默氏病的阶段。这一研究成果于2020年11月13日在线发表在国际学术期刊《细胞》上。

为了阐明Tau亚型和翻译后修饰（PTM）化学计量在阿尔茨海默氏病（AD）中的作用，研究人员生成了Tau多种同工型的95个PTM高分辨率定量蛋白质组学图谱，这些蛋白从49个AD和42个对照受试者的死后人体组织中分离而来。尽管Tau PTM图显示了受试者之间的异质性，但PTM的一个子集显示出较高的AD阳性率和频率，从而表明在疾病中的重要性。无监督分析表明PTM有序地发生，导致Tau聚集。

总之，这项研究鉴定出在疾病不同阶段对疾病干预至关重要的Tau蛋白特征，包括0N和4R亚型的富集、C末端的代表性不足、脯氨酸丰富区（PRR）中负电荷的增加，以及微管结合域（MBD）中正电荷的减少。

附：英文原文

Title: Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease

Author: Hendrik Wesseling, Waltraud Mair, Mukesh Kumar, Christoph N. Schlaffner, Shaojun Tang, Pieter Beerepoot, Benoit Fatou, Amanda J. Guise, Long Cheng, Shuko Takeda, Jan Muntel, Melissa S. Rotunno, Simon Dujardin, Peter Davies, Kenneth S. Kosik, Bruce L. Miller, Sabina Berretta, John C. Hedreen, Lea T. Grinberg, William W. Seeley, Bradley T. Hyman, Hanno Steen, Judith A. Steen

Issue&Volume: 2020-11-13

Abstract: To elucidate the role of Tau isoforms and post-translational modification (PTM) stoichiometryin Alzheimer’s disease (AD), we generated a high-resolution quantitative proteomicsmap of 95 PTMs on multiple isoforms of Tau isolated from postmortem human tissue from49 AD and 42 control subjects. Although Tau PTM maps reveal heterogeneity across subjects,a subset of PTMs display high occupancy and frequency for AD, suggesting importancein disease. Unsupervised analyses indicate that PTMs occur in an ordered manner, leadingto Tau aggregation. The processive addition and minimal set of PTMs associated withseeding activity was further defined by analysis of size-fractionated Tau. To summarize,features in the Tau protein critical for disease intervention at different stagesof disease are identified, including enrichment of 0N and 4R isoforms, underrepresentationof the C terminus, an increase in negative charge in the proline-rich region (PRR),and a decrease in positive charge in the microtubule binding domain (MBD).

DOI: 10.1016/j.cell.2020.10.029

Source: https://www.cell.com/cell/fulltext/S0092-8674(20)31393-3