美国哥伦比亚大学Anthony W.P. Fitzpatrick和美国梅奥诊所Leonard Petrucelli合作发现翻译后修饰介导Tau蛋白病种类的结构多样性。这一研究成果2020年2月6日在线发表在国际学术期刊《细胞》上。

研究人员使用冷冻电镜（cryo-EM）确定了人脑组织皮质基底节变性（CBD）病中tau细丝的结构。CBD tau细丝的冷冻电镜和质谱分析表明，该构象异构体存在大量的翻译后修饰（PTM），这帮助研究人员将PTM直接映射到结构上。通过比较来自CBD和阿尔茨海默氏病的tau细丝结构和PTM，研究人员发现tau的泛素化可以介导原丝间的界面。基于此，研究人员提出了一个结构模型，其中PTM之间的串扰影响tau丝结构，这有助于tau蛋白病的结构多样性。该研究为进一步阐明多态性原纤维的结构（包括其PTM）与神经退行性疾病之间的关系建立了基石。

据悉，Tau聚集为不溶性细丝是Tau蛋白病的标志性病理特征。然而，尚不知道什么控制与个体Tau蛋白病相关特异性结构的形成和序列聚集。

附：英文原文

Title: Posttranslational Modifications Mediate the Structural Diversity of Tauopathy Strains

Author: Tamta Arakhamia, Christina E. Lee, Yari Carlomagno, Duc M. Duong, Sean R. Kundinger, Kevin Wang, Dewight Williams, Michael DeTure, Dennis W. Dickson, Casey N. Cook, Nicholas T. Seyfried, Leonard Petrucelli, Anthony W.P. Fitzpatrick

Issue&Volume: February 06, 2020

Abstract: Tau aggregation into insoluble filaments is the defining pathological hallmark oftauopathies. However, it is not known what controls the formation and templated seedingof strain-specific structures associated with individual tauopathies. Here, we usecryo-electron microscopy (cryo-EM) to determine the structures of tau filaments fromcorticobasal degeneration (CBD) human brain tissue. Cryo-EM and mass spectrometryof tau filaments from CBD reveal that this conformer is heavily decorated with posttranslationalmodifications (PTMs), enabling us to map PTMs directly onto the structures. By comparingthe structures and PTMs of tau filaments from CBD and Alzheimer’s disease, it is foundthat ubiquitination of tau can mediate inter-protofilament interfaces. We proposea structure-based model in which cross-talk between PTMs influences tau filament structure,contributing to the structural diversity of tauopathy strains. Our approach establishesa framework for further elucidating the relationship between the structures of polymorphicfibrils, including their PTMs, and neurodegenerative disease.

DOI: 10.1016/j.cell.2020.01.027

Source: https://www.cell.com/cell/fulltext/S0092-8674(20)30108-2