Targeting protein aggregation for the treatment of degenerative diseases

The misfolding and aggregation of specific proteins — a process known as amyloidogenesis — seem to underlie a range of degenerative disorders. Here, Kelly and colleagues discuss the current understanding of the process and pathological role of protein aggregation, focusing on emerging disease-modifying strategies to ameliorate aggregation-associated degenerative disorders. The aggregation of specific proteins is hypothesized to underlie several degenerative diseases, which are collectively known as amyloid disorders. However, the mechanistic connection between the process of protein aggregation and tissue degeneration is not yet fully understood. Here, we review current and emerging strategies to ameliorate aggregation-associated degenerative disorders, with a focus on disease-modifying strategies that prevent the formation of and/or eliminate protein aggregates. Persuasive pharmacological and genetic evidence now supports protein aggregation as the cause of postmitotic tissue dysfunction or loss. However, a more detailed understanding of the factors that trigger and sustain aggregate formation and of the structure–activity relationships underlying proteotoxicity is needed to develop future disease-modifying therapies.