F.M. Kirby Neurobiology Center, Department of Neurobiology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
F.M. Kirby Neurobiology Center, Department of Neurobiology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Pathology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Cell. 2020 Dec 10;183(6):1699-1713.e13. doi: 10.1016/j.cell.2020.10.029. Epub 2020 Nov 13.
To elucidate the role of Tau isoforms and post-translational modification (PTM) stoichiometry in Alzheimer's disease (AD), we generated a high-resolution quantitative proteomics map of 95 PTMs on multiple isoforms of Tau isolated from postmortem human tissue from 49 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 importance in disease. Unsupervised analyses indicate that PTMs occur in an ordered manner, leading to Tau aggregation. The processive addition and minimal set of PTMs associated with seeding activity was further defined by analysis of size-fractionated Tau. To summarize, features in the Tau protein critical for disease intervention at different stages of disease are identified, including enrichment of 0N and 4R isoforms, underrepresentation of 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).
为了阐明 Tau 异构体和翻译后修饰（PTM）化学计量在阿尔茨海默病（AD）中的作用，我们从 49 名 AD 患者和 42 名对照患者的死后组织中分离出 Tau 的多个异构体，生成了 Tau 上 95 种 PTM 的高分辨率定量蛋白质组图谱。尽管 Tau PTM 图谱在不同个体之间显示出异质性，但一组 PTMs 在 AD 中显示出高占有率和高频率，表明它们在疾病中很重要。无监督分析表明，PTMs 按顺序发生，导致 Tau 聚集。通过对大小分级的 Tau 进行分析，进一步定义了与成核活性相关的连续添加和最小 PTM 集。总之，确定了 Tau 蛋白中在疾病的不同阶段对疾病干预至关重要的特征，包括 0N 和 4R 异构体的富集、C 端的代表性降低、富含脯氨酸区域（PRR）的负电荷增加以及微管结合域（MBD）的正电荷减少。
