Kinetics of Amyloid Oligomer Formation.

IF 10.4 1区 生物学 Q1 BIOPHYSICS
Jiapeng Wei, Georg Meisl, Alexander J Dear, Thomas C T Michaels, Tuomas P J Knowles
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引用次数: 0

Abstract

Low-molecular-weight oligomers formed from amyloidogenic peptides and proteins have been identified as key cytotoxins across a range of neurodegenerative disorders, including Alzheimer's disease and Parkinson's disease. Developing therapeutic strategies that target oligomers is therefore emerging as a promising approach for combating protein misfolding diseases. As such, there is a great need to understand the fundamental properties, dynamics, and mechanisms associated with oligomer formation. In this review, we discuss how chemical kinetics provides a powerful tool for studying these systems. We review the chemical kinetics approach to determining the underlying molecular pathways of protein aggregation and discuss its applications to oligomer formation and dynamics. We discuss how this approach can reveal detailed mechanisms of primary and secondary oligomer formation, including the role of interfaces in these processes. We further use this framework to describe the processes of oligomer conversion and dissociation, and highlight the distinction between on-pathway and off-pathway oligomers. Furthermore, we showcase on the basis of experimental data the diversity of pathways leading to oligomer formation in various in vitro and in silico systems. Finally, using the lens of the chemical kinetics framework, we look at the current oligomer inhibitor strategies both in vitro and in vivo.

淀粉样蛋白低聚物形成动力学。
由淀粉样蛋白肽和蛋白质形成的低分子量低聚物已被确定为一系列神经退行性疾病(包括阿尔茨海默病和帕金森病)的关键细胞毒素。因此,开发针对低聚物的治疗策略正在成为对抗蛋白质错误折叠疾病的一种有希望的方法。因此,非常需要了解与低聚物形成相关的基本性质、动力学和机制。在这篇综述中,我们讨论了化学动力学如何为研究这些系统提供了一个强有力的工具。我们回顾了化学动力学方法来确定蛋白质聚集的潜在分子途径,并讨论了其在低聚物形成和动力学方面的应用。我们讨论了这种方法如何揭示初级和次级低聚物形成的详细机制,包括界面在这些过程中的作用。我们进一步使用这一框架来描述低聚物转化和解离的过程,并强调了通路上和通路外低聚物之间的区别。此外,我们在实验数据的基础上展示了在各种体外和硅系统中导致低聚物形成的途径的多样性。最后,使用化学动力学框架的镜头,我们看看目前的低聚物抑制剂策略在体外和体内。
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来源期刊
Annual Review of Biophysics
Annual Review of Biophysics 生物-生物物理
CiteScore
21.00
自引率
0.00%
发文量
25
期刊介绍: The Annual Review of Biophysics, in publication since 1972, covers significant developments in the field of biophysics, including macromolecular structure, function and dynamics, theoretical and computational biophysics, molecular biophysics of the cell, physical systems biology, membrane biophysics, biotechnology, nanotechnology, and emerging techniques.
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