Abstract
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 invivo, 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.
Highlights
Neurodegenerative disorders are increasingly prevalent in our society and represent a very significant challenge to healthcare systems (Balch et al, 2008; Dobson, 2003)
One common feature associated with these conditions, is the aggregation of certain peptides and proteins, which generates a cascade of pathological events, including the secondary aggregation of various other proteins and the consequent failure of protein homeostasis to preserve normal biological function (Balch et al, 2008; Dobson, 2003; Gidalevitz et al, 2006; Selkoe, 2011)
We find through our analysis of the human and C. elegans proteomes that those proteins known to interact with aggregates or to aggregate upon aging are highly supersaturated, and that the cellular processes known to be associated with neurodegenerative diseases are at risk of disruption because they involve an exceptionally large number of supersaturated proteins
Summary
Neurodegenerative disorders are increasingly prevalent in our society and represent a very significant challenge to healthcare systems (Balch et al, 2008; Dobson, 2003). The various sets of aggregating proteins may correspond to a fraction of the proteome with distinctive characteristics that increase the risk of aggregation under many kinds of stress. The latter possibility is consistent with observations that aggregation-prone proteins share general physicochemical features (Chiti et al, 2003; Fernandez-Escamilla et al, 2004; Olzscha et al, 2011; Tartaglia et al, 2008)
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