Proteome Metastability in Health, Aging, and Disease

Abstract

Maintaining protein solubility is fundamental to proteostasis, as the formation of diverse aggregated species is associated with a variety of cytotoxic events and disorders, including Alzheimer's and Parkinson's diseases. Increasing evidence indicates that protein aggregation can be widespread in living systems, as many different proteins aggregate upon cellular stress. The origins of this proteomic metastability, however, remain unclear, as do the reasons only certain proteins aggregate in vivo. We have applied simple models of cotranslational folding and protein supersaturation to quantify metastability at a proteome scale. We find that many proteins can shift from cotranslational to posttranslational folding because of translation kinetics, a source of metastability for nascent chains. Further, we show that the proteins most vulnerable to aggregation are those whose cellular concentrations are high relative to their intrinsic solubilities. These supersaturated proteins constitute a metastable sub-proteome involved in forming pathological assemblies in stress and ageing. We find that such proteins are overrepresented in the biochemical processes associated with neurodegenerative disorders, helping to rationalise their specific cellular pathologies. We anticipate that this type of analysis can provide a generally applicable basis for tracking the instability of proteomes in ageing, stress, and disease.View Large Image | View Hi-Res Image | Download PowerPoint Slide