Defining the Neuropathological Aggresome across in Silico, in Vitro, and ex Vivo Experiments.
Defining the Neuropathological Aggresome across in Silico, in Vitro, and ex Vivo Experiments.
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DOI：
10.1021/acs.jpcb.0c09193
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发表时间：
2021-03-04
期刊：
影响因子：
--
通讯作者：
Levine ZA
中科院分区：
文献类型：
--
作者：
Gomes GN;Levine ZA
在生命过程中蛋白质稳态的丧失与广泛的使人衰弱的退行性疾病相关，并且是人类衰老的中心标志。如果不加以控制，本质上无序的蛋白质可以在病理上聚集成高度有序的原纤维、斑块和缠结（称为淀粉样蛋白），这与无数疾病有关，如阿尔茨海默病、帕金森病、II型糖尿病、癌症，甚至某些病毒感染。然而，尽管蛋白质折叠和溶液生物物理学技术取得了重大进展，但确定人类这些疾病的分子原因仍然难以捉摸。这部分是由于最近的发现表明，可溶性蛋白质低聚物，而不是不溶性纤维或斑块，驱动大多数病理过程。这随后导致研究人员转而关注异质性和经常混杂的蛋白质寡聚体。不幸的是，在如何以系统的方式制备、建模、实验证实和提取与人类疾病相关的淀粉样蛋白寡聚体方面仍然存在重大差距。本综述将报告这些技术中的每一种及其成功和缺点，以试图标准化跨学科的蛋白质寡聚体之间的比较，特别是在神经退行性变的背景下。通过标准化多种技术并识别它们的共同重叠，可以构建可溶性神经病理性侵袭组的更清晰图像，并将其用作研究人类疾病和衰老的基线。
The loss of proteostasis over the life course is associated with a wide range of debilitating degenerative diseases and is a central hallmark of human aging. When left unchecked, proteins that are intrinsically disordered can pathologically aggregate into highly ordered fibrils, plaques, and tangles (termed amyloids), which are associated with countless disorders such as Alzheimer’s Disease, Parkinson’s Disease, Type II Diabetes, cancer, and even certain viral infections. However, despite significant advances in protein folding and solution biophysics techniques, determining the molecular cause of these conditions in humans has remained elusive. This has been due, in part, to recent discoveries showing that soluble protein oligomers, not insoluble fibrils or plaques, drive the majority of pathological processes. This has subsequently led researchers to focus instead on heterogeneous and often promiscuous protein oligomers. Unfortunately, significant gaps remain in how to prepare, model, experimentally corroborate, and extract amyloid oligomers relevant to human disease in a systematic manner. This review will report on each of these techniques and their successes and shortcomings in an attempt to standardize comparisons between protein oligomers across disciplines, especially in the context of neurodegeneration. By standardizing multiple techniques and identifying their common overlap, a clearer picture of the soluble neuropathological aggresome can be constructed and used as a baseline for studying human disease and aging.
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影响因子：
2.7
作者：
Bolhuis, PG;Dellago, C;Chandler, D
通讯作者：
Chandler, D
影响因子：
5.5
作者：
Carballo-Pacheco, Martin;Ismail, Ahmed E.;Strodel, Birgit
通讯作者：
Strodel, Birgit
影响因子：
5.5
作者：
Bitan, G;Fradinger, EA;Teplow, DB
通讯作者：
Teplow, DB
影响因子：
5.6
作者：
BARROW, CJ;YASUDA, A;ZAGORSKI, MG
通讯作者：
ZAGORSKI, MG
DOI：
10.1039/c4cp05563b
发表时间：
2015-03-28
期刊：
Physical chemistry chemical physics : PCCP
影响因子：
--
作者：
Arosio P;Knowles TP;Linse S
通讯作者：
Linse S