The Amyloid Phenomenon and Its Links with Human Disease

The ability of normally soluble proteins to convert into amyloid fibrils is now recognized to be a generic phenomenon. The overall cross-β architecture of the core elements of such structures is closely similar for different amino acid sequences, as this architecture is dominated by interactions associated with the common polypeptide main chain. In contrast, the multiplicity of complex and intricate structures of the functional states of proteins is dictated by specific interactions involving the variable side chains, the sequence of which is unique to a given protein. Nevertheless, the side chains dictate important aspects of the amyloid structure, including the regions of the sequence that form the core elements of the fibrils and the kinetics and mechanism of the conversion process. The formation of the amyloid state of proteins is of particular importance in the context of a range of medical disorders that include Alzheimer's and Parkinson's diseases and type 2 diabetes. These disorders are becoming increasingly common in the modern world, primarily as a consequence of increasing life spans and changing lifestyles, and now affect some 500 million people worldwide. This review describes recent progress in our understanding of the molecular origins of these conditions and discusses emerging ideas for new and rational therapeutic strategies by which to combat their onset and progression.