Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom.
Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138.
Proc Natl Acad Sci U S A. 2020 Jun 2;117(22):12087-12094. doi: 10.1073/pnas.1922267117. Epub 2020 May 15.
The spontaneous assembly of proteins into amyloid fibrils is a phenomenon central to many increasingly common and currently incurable human disorders, including Alzheimer's and Parkinson's diseases. Oligomeric species form transiently during this process and not only act as essential intermediates in the assembly of new filaments but also represent major pathogenic agents in these diseases. While amyloid fibrils possess a common, defining set of physicochemical features, oligomers, by contrast, appear much more diverse, and their commonalities and differences have hitherto remained largely unexplored. Here, we use the framework of chemical kinetics to investigate their dynamical properties. By fitting experimental data for several unrelated amyloidogenic systems to newly derived mechanistic models, we find that oligomers present with a remarkably wide range of kinetic and thermodynamic stabilities but that they possess two properties that are generic: they are overwhelmingly nonfibrillar, and they predominantly dissociate back to monomers rather than maturing into fibrillar species. These discoveries change our understanding of the relationship between amyloid oligomers and amyloid fibrils and have important implications for the nature of their cellular toxicity.
蛋白质自发组装成淀粉样纤维是许多日益常见且目前无法治愈的人类疾病（包括阿尔茨海默病和帕金森病）的核心现象。在这个过程中，寡聚体形成短暂存在，不仅是新纤维组装的重要中间产物，而且是这些疾病的主要致病因子。虽然淀粉样纤维具有共同的、定义明确的一组物理化学特征，但寡聚体则显得更加多样化，它们的共性和差异迄今在很大程度上仍未得到探索。在这里，我们使用化学动力学的框架来研究它们的动力学特性。通过将几个不相关的淀粉样蛋白系统的实验数据拟合到新推导的机械模型中，我们发现寡聚体表现出非常广泛的动力学和热力学稳定性，但它们具有两个普遍存在的特性：它们绝大多数是非纤维状的，并且它们主要解离回单体，而不是成熟为纤维状物种。这些发现改变了我们对淀粉样寡聚体和淀粉样纤维之间关系的理解，并对它们的细胞毒性性质具有重要意义。
