Misfolded protein oligomers: mechanisms of formation, cytotoxic effects, and pharmacological approaches against protein misfolding diseases

Abstract

The conversion of native peptides and proteins into amyloid aggregates is a hallmark of over 50 human disorders, including Alzheimer's and Parkinson's diseases. Increasing evidence implicates misfolded protein oligomers produced during the amyloid formation process as the primary cytotoxic agents in many of these devastating conditions. In this review, we analyze the processes by which oligomers are formed, their structures, physicochemical properties, population dynamics, and the mechanisms of their cytotoxicity. We then focus on drug discovery strategies that target the formation of oligomers and their ability to disrupt cell physiology and trigger degenerative processes.

Keywords: Aggregation kinetics; Amyloid toxicity; Biophysics; Cellular interactions; Diagnostics; Drug discovery; Fibril fragmentation; Lecanemab; Protofibrils; Secondary nucleation; Therapeutics.