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

Greet De Baets,Frederic Rousseau,Joost Schymkowitz,Loic Van Doorn,Guanghong Wei

doi:10.1371/journal.pcbi.1004374

Greet De Baets, Frederic Rousseau + Show 3 more

Open Access

https://doi.org/10.1371/journal.pcbi.1004374

Copy DOI

Abstract

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.

Highlights

Protein aggregation is found to be associated to an increasing number of human diseases [1]
Protein aggregation has been recognized to contribute to the development of more than 30 human diseases such as Alzheimer and Parkinson disease
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

Summary

Introduction

Protein aggregation is found to be associated to an increasing number of human diseases [1]. The mode of action of these protein aggregates in disease is generally classified into loss-of-function and gain-of-function effects [2]. Aggregated proteins can acquire novel aggregation-specific functions that further contribute to the disease. In this case, the presence of an aggregated protein results in a worse disease outcome than the absence of the native protein. In Alzheimer disease for example, Aβ peptide aggregation generates synaptotoxic activity leading to neurodegeneration, while absence of the Aβ peptide does not result in neuronal loss. It was found that non-amyloid aggregation of p53 confers oncogenic gain-offunction activity to tumors resulting in increased cell proliferation rather than apoptosis [4]. In familial Fabry disease, an archetypical loss-of-function disease resulting from α-galactosidase inactivation, aggregating mutants acquire gain-of-function in the form of pharmacological resistance to the chemical chaperone DGJ-1[5]

Methods

Results

Discussion

Conclusion