英国利兹大学Neil A. Ranson等研究人员合作揭示淀粉样蛋白组装过程中纤维多态性的结构演变。2023年12月21日出版的《细胞》杂志发表了这项成果。

研究人员利用冷冻电镜（cryo-EM）测定了人胰岛淀粉样多肽（IAPP-S20G）的一种疾病相关变体在体外纤化过程中不同时期的淀粉样纤维结构。引人注目的是，在滞后期、生长期和高原期形成的纤维具有不同的结构，随着纤化的进行，新的形式出现，而其他形式则消失。野生型hIAPP的时间过程也显示纤维随时间变化，这表明这是IAPP淀粉样组装的一般特性。对瞬时填充的纤维结构的观察有助于了解淀粉样蛋白的组装机制，并有可能为淀粉样蛋白在疾病中的发展提供新的见解。

据了解，cryo-EM为淀粉样蛋白纤维结构（包括与疾病相关的纤维结构）提供了前所未有的洞察力。然而，这些结构是漫长组装过程的终点，它们与组装早期形成的纤维的关系尚不清楚。因此，在组装过程中是否会形成具有潜在不同病理特性的不同纤维结构仍是未知数。

附：英文原文

Title: Structural evolution of fibril polymorphs during amyloid assembly

Author: Martin Wilkinson, Yong Xu, Dev Thacker, Alexander I.P. Taylor, Declan G. Fisher, Rodrigo U. Gallardo, Sheena E. Radford, Neil A. Ranson

Issue&Volume: 2023/12/21

Abstract: Cryoelectron microscopy (cryo-EM) has provided unprecedented insights into amyloid fibril structures, including those associated with disease. However, these structures represent the endpoints of long assembly processes, and their relationship to fibrils formed early in assembly is unknown. Consequently, whether different fibril architectures, with potentially different pathological properties, form during assembly remains unknown. Here, we used cryo-EM to determine structures of amyloid fibrils at different times during in vitro fibrillation of a disease-related variant of human islet amyloid polypeptide (IAPP-S20G). Strikingly, the fibrils formed in the lag, growth, and plateau phases have different structures, with new forms appearing and others disappearing as fibrillation proceeds. A time course with wild-type hIAPP also shows fibrils changing with time, suggesting that this is a general property of IAPP amyloid assembly. The observation of transiently populated fibril structures has implications for understanding amyloid assembly mechanisms with potential new insights into amyloid progression in disease.

DOI: 10.1016/j.cell.2023.11.025

Source: https://www.cell.com/cell/fulltext/S0092-8674(23)01311-9