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Protein Misfolding, Amyloid Formation, and Human Disease: A Summary of Progress Over the Last Decade
Annual Review of Biochemistry ( IF 12.1 ) Pub Date : 2017-06-27 00:00:00 , DOI: 10.1146/annurev-biochem-061516-045115
Fabrizio Chiti 1 , Christopher M. Dobson 2
Affiliation  

Peptides and proteins have been found to possess an inherent tendency to convert from their native functional states into intractable amyloid aggregates. This phenomenon is associated with a range of increasingly common human disorders, including Alzheimer and Parkinson diseases, type II diabetes, and a number of systemic amyloidoses. In this review, we describe this field of science with particular reference to the advances that have been made over the last decade in our understanding of its fundamental nature and consequences. We list the proteins that are known to be deposited as amyloid or other types of aggregates in human tissues and the disorders with which they are associated, as well as the proteins that exploit the amyloid motif to play specific functional roles in humans. In addition, we summarize the genetic factors that have provided insight into the mechanisms of disease onset. We describe recent advances in our knowledge of the structures of amyloid fibrils and their oligomeric precursors and of the mechanisms by which they are formed and proliferate to generate cellular dysfunction. We show evidence that a complex proteostasis network actively combats protein aggregation and that such an efficient system can fail in some circumstances and give rise to disease. Finally, we anticipate the development of novel therapeutic strategies with which to prevent or treat these highly debilitating and currently incurable conditions.

中文翻译:


蛋白质错误折叠,淀粉样蛋白形成和人类疾病:最近十年的进展总结

已发现肽和蛋白质具有从其天然功能状态转变为难处理的淀粉样聚集体的固有趋势。这种现象与一系列越来越常见的人类疾病有关,包括阿尔茨海默氏症和帕金森氏病,II型糖尿病和许多全身性淀粉样蛋白。在这篇评论中,我们描述了这个科学领域,特别参考了过去十年我们在理解科学的基本性质和后果方面所取得的进步。我们列出了已知会以淀粉样蛋白或其他类型的聚集体形式沉积在人体组织中的蛋白质以及与之相关的疾病,以及利用淀粉样蛋白基序在人类中发挥特定功能作用的蛋白质。此外,我们总结了遗传因素,这些因素提供了对疾病发作机制的深入了解。我们描述了我们对淀粉样蛋白原纤维及其寡聚前体的结构及其形成和增殖以产生细胞功能障碍的机制的知识的最新进展。我们显示出证据,复杂的蛋白质稳定网络可以有效地对抗蛋白质聚集,并且这种有效的系统在某些情况下可能会失败并引起疾病。最后,我们预计将开发出预防或治疗这些高度虚弱和目前无法治愈的疾病的新型治疗策略。我们描述了我们对淀粉样蛋白原纤维及其寡聚前体的结构及其形成和增殖以产生细胞功能障碍的机制的知识的最新进展。我们显示出证据,复杂的蛋白质稳定网络可以有效地对抗蛋白质聚集,并且这种有效的系统在某些情况下可能会失败并引起疾病。最后,我们预计将开发出预防或治疗这些高度虚弱和目前无法治愈的疾病的新型治疗策略。我们描述了我们对淀粉样蛋白原纤维及其寡聚前体的结构及其形成和增殖以产生细胞功能障碍的机制的知识的最新进展。我们显示出证据,复杂的蛋白质稳定网络可以有效地对抗蛋白质聚集,并且这种有效的系统在某些情况下可能会失败并引起疾病。最后,我们预计将开发出预防或治疗这些高度虚弱和目前无法治愈的疾病的新型治疗策略。

更新日期:2017-06-27
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