The maintenance of protein solubility is a fundamental aspect of cellular homeostasis because protein aggregation is associated with a wide variety of human diseases. Numerous proteins unrelated in sequence and structure, however, can misfold and aggregate, and widespread aggregation can occur in living systems under stress or aging. A crucial question in this context is why only certain proteins appear to aggregate readily in vivo, whereas others do not. We identify here the proteins most vulnerable to aggregation as those whose cellular concentrations are high relative to their solubilities. We find that these supersaturated proteins represent a metastable subproteome involved in pathological aggregation during stress and aging and are overrepresented in biochemical processes associated with neurodegenerative disorders. Consequently, such cellular processes become dysfunctional when the ability to keep intrinsically supersaturated proteins soluble is compromised. Thus, the simultaneous analysis of abundance and solubility can rationalize the diverse cellular pathologies linked to neurodegenerative diseases and aging.

P.C. was supported by grants from the US-UK Fulbright Commission and St. John’s College, University of Cambridge. R.I.M. was supported by grants from the National Institutes of Health (NIGMS, NIA, and NINDS), the Ellison Medical Foundation, and the Daniel F. and Ada L. Rice Foundation. C.M.D. and M.V. were supported by grants from the Wellcome Trust and the UK Biotechnology and Biological Sciences Research Council.