Amyloid misfolding, aggregation, and the early onset of protein deposition diseases: insights from AFM experiments and computational analyses

IF 0.7 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY
Y. Lyubchenko
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引用次数: 12

Abstract

The development of Alzheimer’s disease is believed to be caused by the assembly of amyloid β proteins into aggregates and the formation of extracellular senile plaques. Similar models suggest that structural misfolding and aggregation of proteins are associated with the early onset of diseases such as Parkinson’s, Huntington’s, and other protein deposition diseases. Initially, the aggregates were structurally characterized by traditional techniques such as x-ray crystallography, NMR, electron microscopy, and AFM. However, data regarding the structures formed during the early stages of the aggregation process were unknown. Experimental models of protein deposition diseases have demonstrated that the small oligomeric species have significant neurotoxicity. This highlights the urgent need to discover the properties of these species, to enable the development of efficient diagnostic and therapeutic strategies. The oligomers exist transiently, making it impossible to use traditional structural techniques to study their characteristics. The recent implementation of single-molecule imaging and probing techniques that are capable of probing transient states have enabled the properties of these oligomers to be characterized. Additionally, powerful computational techniques capable of structurally analyzing oligomers at the atomic level advanced our understanding of the amyloid aggregation problem. This review outlines the progress in AFM experimental studies and computational analyses with a primary focus on understanding the very first stage of the aggregation process. Experimental approaches can aid in the development of novel sensitive diagnostic and preventive strategies for protein deposition diseases, and several examples of these approaches will be discussed.
淀粉样蛋白错误折叠、聚集和蛋白质沉积疾病的早期发病:来自原子力显微镜实验和计算分析的见解
阿尔茨海默病的发展被认为是由β淀粉样蛋白聚集成聚集体和细胞外老年斑的形成引起的。类似的模型表明,蛋白质的结构错误折叠和聚集与帕金森病、亨廷顿病和其他蛋白质沉积病等疾病的早期发病有关。最初,聚集体的结构特征是通过传统的技术,如x射线晶体学,核磁共振,电子显微镜和原子力显微镜。然而,在聚集过程的早期阶段形成的结构的数据是未知的。蛋白质沉积疾病的实验模型表明,小寡聚物种具有显著的神经毒性。这凸显了迫切需要发现这些物种的特性,以便开发有效的诊断和治疗策略。低聚物的存在是短暂的,因此不可能使用传统的结构技术来研究它们的特性。最近实现的单分子成像和探测技术能够探测瞬态,使这些低聚物的性质得以表征。此外,强大的计算技术能够在原子水平上分析低聚物的结构,这提高了我们对淀粉样蛋白聚集问题的理解。这篇综述概述了原子力显微镜实验研究和计算分析的进展,主要集中在理解聚集过程的第一阶段。实验方法可以帮助开发新的敏感的蛋白质沉积疾病诊断和预防策略,并将讨论这些方法的几个例子。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
AIMS Molecular Science
AIMS Molecular Science BIOCHEMISTRY & MOLECULAR BIOLOGY-
自引率
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4
审稿时长
5 weeks
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