The Amyloid Phenomenon and Its Links with Human Disease

Abstract

The ability of normally soluble proteins to convert into amyloid fibrils is now recognized to be a generic phenomenon. The overall cross-b 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.

Stochastic calculus of protein filament formation under spatial confinement

“…Many bacteria also exploit protein filaments during biofilm formation [12]. However, deregulated protein filament aggregation can be implicated in a number of human disorders [13][14][15][16]. Key examples of such pathologies include Alzheimerʼs disease, Parkinsonʼs disease, sickle-cell anemia and type-II diabetes, which are associated with the formation in the human brain or other organs of filamentous protein assemblies commonly known as amyloid fibrils [13][14][15][16][17][18][19][20][21][22][23][24].…”

Self‐assembly of β‐turn motif‐connected tandem repeats of Aβ16‐22 and its aromatic analogs

“…Amyloid aggregates have been long known to be the causative agents of many human diseases. [41] Despite several decades of research on amyloid aggregates, we are far from completely understanding the process of protein assembly into amyloid fibrils and consequently development of therapeutic agents. Growing evidence in past decade about the functional roles of amyloids indicates that it is not an alien-fold.…”

Physical mechanisms of amyloid nucleation on fluid membranes

“…The aggregation of normally soluble proteins into βsheet rich amyloid fibrils is a common form of protein assembly that has broad implications across biomedical and biotechnological sciences, in context as diverse as the molecular origins of neurodegenerative disorders to the production of functional materials [1,2]. The presence of surfaces and interfaces can strongly influence amyloid aggregation, either catalysing or inhibiting it, depending on the nature of the surface.…”