Proteostasis impairment in protein-misfolding and -aggregation diseases

•Cells possess a complex proteostasis network (PN) to ensure protein homeostasis.•Aggregates permanently engage molecular chaperones and other PN components.•The PN is challenged by chronic stress in protein-aggregation diseases and aging.•Overtaxing the PN drives a vicious cycle of disease progression with eventual proteostasis collapse.

Cells possess an extensive network of components to safeguard proteome integrity and maintain protein homeostasis (proteostasis). When this proteostasis network (PN) declines in performance, as may be the case during aging, newly synthesized proteins are no longer able to fold efficiently and metastable proteins lose their functionally active conformations, particularly under conditions of cell stress. Apart from loss-of-function effects, a critical consequence of PN deficiency is the accumulation of cytotoxic protein aggregates, which are also associated with many age-dependent neurodegenerative diseases and other medical disorders. Here we discuss recent evidence that the chronic production of aberrantly folded and aggregated proteins in these diseases is harmful by overtaxing PN capacity, setting in motion a vicious cycle of increasing proteome imbalance that eventually leads to PN collapse and cell death.