Increased Aggregation Is More Frequently Associated to Human Disease-Associated Mutations Than to Neutral Polymorphisms

Protein aggregation is a hallmark of over 30 human pathologies. In these diseases, the aggregation of one or a few specific proteins is often toxic, leading to cellular degeneration and/or organ disruption in addition to the loss-of-function resulting from protein misfolding. Although the pathophysiological consequences of these diseases are overt, the molecular dysregulations leading to aggregate toxicity are still unclear and appear to be diverse and multifactorial. The molecular mechanisms of protein aggregation and therefore the biophysical parameters favoring protein aggregation are better understood. Here we perform an in silico survey of the impact of human sequence variation on the aggregation propensity of human proteins. We find that disease-associated variations are statistically significantly enriched in mutations that increase the aggregation potential of human proteins when compared to neutral sequence variations. These findings suggest that protein aggregation might have a broader impact on human disease than generally assumed and that beyond loss-of-function, the aggregation of mutant proteins involved in cancer, immune disorders or inflammation could potentially further contribute to disease by additional burden on cellular protein homeostasis.
Author Summary Protein aggregation has been recognized to contribute to the development of more than 30 human diseases such as Alzheimer and Parkinson disease. Here we have performed an in silico survey of human sequence variations to evaluate whether protein aggregation might impact human disease beyond the above-mentioned aggregation diseases. We find that human disease mutations are more likely to increase the aggregation potential of proteins than non-disease associated mutations. This survey therefore suggests the possibility that protein aggregation is a more widespread disease modifier than previously expected.