Increased Aggregation Is More Frequently Associated to Human Disease-Associated Mutations Than to Neutral Polymorphisms.
Increased Aggregation Is More Frequently Associated to Human Disease-Associated Mutations Than to Neutral Polymorphisms.
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DOI：
10.1371/journal.pcbi.1004374
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发表时间：
2015-09
影响因子：
4.3
通讯作者：
Schymkowitz J
中科院分区：
文献类型：
--
作者：
De Baets G;Van Doorn L;Rousseau F;Schymkowitz J
蛋白质聚集是30多种人类疾病的标志。在这些疾病中，一种或几种特定蛋白质的聚集往往是有毒的，除了蛋白质错误折叠导致的功能丧失外，还会导致细胞退化和/或器官破坏。虽然这些疾病的病理生理后果是明确的，但导致聚集毒性的分子失调仍不清楚，而且似乎是多样化的和多因素的。蛋白质聚集的分子机制以及因此有利于蛋白质聚集的生物物理参数被更好地理解。在这里，我们进行了一项关于人类序列变异对人类蛋白质聚集倾向的影响的电子调查。我们发现，与疾病相关的变异在统计上显著丰富，与中性序列变异相比，这些突变增加了人类蛋白质的聚集潜力。这些发现表明，蛋白质聚集对人类疾病的影响可能比通常认为的更广泛，除了功能丧失之外，参与癌症、免疫紊乱或炎症的突变蛋白质的聚集可能通过增加细胞蛋白质稳态的额外负担而进一步导致疾病。蛋白质聚集已被认为有助于30多种人类疾病的发展，如阿尔茨海默病和帕金森病。在这里，我们对人类序列变异进行了电子计算机调查，以评估蛋白质聚集是否会影响上述聚集性疾病以外的人类疾病。我们发现，人类疾病突变比非疾病相关突变更有可能增加蛋白质的聚集潜力。因此，这项调查表明，蛋白质聚集是一种比先前预期更广泛的疾病修饰物的可能性。
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. 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.