Molecular rules governing the structural polymorphism of amyloid fibrils in neurodegenerative diseases

Amyloid fibrils are hallmarks of various neurodegenerative diseases. The structural polymorphism of amyloid fibrils holds significant pathological importance in diseases. This review aims to provide an in-depth overview on the complexity of amyloid fibrils' structural polymorphism and its implications in disease pathogenesis. We firstly decipher the molecular rules governing the structural polymorphism of amyloid fibrils. We then discuss pivotal factors that contribute to the assortment of fibril structural polymorphs, including post-translational modifications (PTMs), disease mutations, and interacting molecules, and elucidate the structural basis of how these determinants influence amyloid fibril polymorphism. Furthermore, we underscore the need for a comprehensive understanding of the relationship between diverse fibril polymorphs and pathological activities, as well as their potential roles in therapeutic applications.