Amyloid aggregation, which disrupts protein homeostasis, is a common pathological event occurring in human neurodegenerative diseases (NDs). Numerous evidences have shown that the structural diversity, so-called polymorphism, is decisive to the amyloid pathology and is closely associated with the onset, progression, and phenotype of ND. But how could one protein form so many stable structures? Recently, atomic structural evidence has been rapidly mounting to depict the involvement of chemical modifications in the amyloid fibril formation. In this Perspective, we aim to present a hierarchical regulation of chemical modifications including covalent post-translational modifications (PTMs) and noncovalent cofactor binding in governing the polymorphic amyloid formation, based mainly on the latest α-synuclein and Tau fibril structures. We hope to emphasize the determinant role of chemical modifications in amyloid assembly and pathology and to evoke chemical biological approaches to lead the fundamental and therapeutic research on protein amyloid state and the associated NDs.

破坏蛋白质稳态的淀粉样蛋白聚集是人类神经退行性疾病（ND）中常见的病理事件。大量证据表明，结构多样性，即所谓的多态性，对淀粉样蛋白病理学具有决定性作用，并与 ND 的发病、进展和表型密切相关。但是一种蛋白质怎么能形成这么多稳定的结构呢？最近，原子结构证据迅速增加，以描述化学修饰参与淀粉样蛋白原纤维的形成。在此观点中，我们旨在提出化学修饰的分级调节，包括共价翻译后修饰 (PTM) 和非共价辅助因子结合，以控制多态性淀粉样蛋白的形成，主要基于最新的 α-突触核蛋白和 Tau 原纤维结构。