Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, MI, U.S.A.
Neuroscience Program, Michigan State University, East Lansing, MI, U.S.A.
Biochem Soc Trans. 2024 Feb 28;52(1):301-318. doi: 10.1042/BST20230596.
Tau protein is associated with many neurodegenerative disorders known as tauopathies. Aggregates of tau are thought of as a main contributor to neurodegeneration in these diseases. Increasingly, evidence points to earlier, soluble conformations of abnormally modified monomers and multimeric tau as toxic forms of tau. The biological processes driving tau from physiological species to pathogenic conformations remain poorly understood, but certain avenues are currently under investigation including the functional consequences of various pathological tau changes (e.g. mutations, post-translational modifications (PTMs), and protein-protein interactions). PTMs can regulate several aspects of tau biology such as proteasomal and autophagic clearance, solubility, and aggregation. Moreover, PTMs can contribute to the transition of tau from normal to pathogenic conformations. However, our understating of how PTMs specifically regulate the transition of tau into pathogenic conformations is partly impeded by the relative lack of structured frameworks to assess and quantify these conformations. In this review, we describe a set of approaches that includes several in vitro assays to determine the contribution of PTMs to tau's transition into known pathogenic conformations. The approaches begin with different methods to create recombinant tau proteins carrying specific PTMs followed by validation of the PTMs status. Then, we describe a set of biochemical and biophysical assays that assess the contribution of a given PTM to different tau conformations, including aggregation, oligomerization, exposure of the phosphatase-activating domain, and seeding. Together, these approaches can facilitate the advancement of our understanding of the relationships between PTMs and tau conformations.
tau 蛋白与许多被称为 tau 病的神经退行性疾病有关。tau 的聚集被认为是这些疾病中神经退行性变的主要原因。越来越多的证据表明，异常修饰的单体和多聚体 tau 的早期可溶性构象是 tau 的毒性形式。驱动 tau 从生理状态向致病构象转变的生物过程仍知之甚少，但目前正在研究某些途径，包括各种病理性 tau 变化（例如突变、翻译后修饰（PTMs）和蛋白质-蛋白质相互作用）的功能后果。PTMs 可以调节 tau 生物学的几个方面，如蛋白酶体和自噬清除、可溶性和聚集。此外，PTMs 可以促进 tau 从正常到致病构象的转变。然而，我们对 PTMs 如何具体调节 tau 向致病构象转变的理解部分受到缺乏评估和量化这些构象的相对缺乏结构化框架的阻碍。在这篇综述中，我们描述了一组方法，包括几种体外测定法，以确定 PTMs 对 tau 向已知致病构象转变的贡献。这些方法从创建携带特定 PTM 的重组 tau 蛋白的不同方法开始，然后验证 PTM 状态。然后，我们描述了一组生化和生物物理测定法，评估给定 PTM 对不同 tau 构象的贡献，包括聚集、寡聚化、磷酸酶激活结构域的暴露和种子形成。这些方法可以促进我们对 PTMs 和 tau 构象之间关系的理解。
