Cell Reports
Volume 5, Issue 3, 14 November 2013, Pages 781-790
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Article
Widespread Aggregation and Neurodegenerative Diseases Are Associated with Supersaturated Proteins

https://doi.org/10.1016/j.celrep.2013.09.043Get rights and content
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Highlights

  • Protein supersaturation is an intrinsic aspect of protein homeostasis

  • Supersaturated proteins form a metastable subproteome

  • Supersaturated proteins are overrepresented in neurodegenerative pathways

  • Supersaturated proteins undergo aggregation upon cellular stress or aging

Summary

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.

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This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.