The solubility of proteins is an essential requirement for their function. Nevertheless, these ubiquitous molecules can undergo aberrant aggregation when the protein homeostasis system becomes impaired. Here we ask: what are the driving forces for protein aggregation in the cellular environment? Emerging evidence suggests that this phenomenon arises at least in part because the native states of many proteins are inherently metastable when their cellular concentrations exceed their critical values. Such 'supersaturated' proteins, which form a 'metastable subproteome', are strongly driven towards aggregation, and are over-represented in specific biochemical pathways associated with neurodegenerative conditions. These observations suggest that effective therapeutic approaches designed to combat neurodegenerative diseases could be aimed at enhancing the ability of the cell to maintain the homeostasis of the metastable subproteome.
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