Gomes Gregory-Neal, Levine Zachary A
Department of Pathology, Yale School of Medicine, New Haven, Connecticut 06520, United States.
Department of Molecular Biophysics & Biochemistry, Yale University, New Haven, Connecticut 06511, United States.
J Phys Chem B. 2021 Mar 4;125(8):1974-1996. doi: 10.1021/acs.jpcb.0c09193. Epub 2021 Jan 19.
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.
蛋白质稳态在生命过程中的丧失与多种使人衰弱的退行性疾病相关，是人类衰老的一个核心标志。如果不加以控制，内在无序的蛋白质会病理聚集成高度有序的纤维、斑块和缠结（称为淀粉样蛋白），这与无数疾病相关，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，但确定人类这些病症的分子病因仍然难以捉摸。部分原因在于最近的发现表明，可溶性蛋白质寡聚体而非不溶性纤维或斑块驱动了大多数病理过程。这随后导致研究人员转而关注异质性且通常混杂的蛋白质寡聚体。不幸的是，在如何系统地制备、模拟、实验证实以及提取与人类疾病相关的淀粉样蛋白寡聚体方面仍存在重大差距。本综述将报告这些技术中的每一种及其成功与不足，试图规范跨学科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。通过规范多种技术并确定它们的共同重叠部分，可以构建出可溶性神经病理聚集体的更清晰图景，并将其用作研究人类疾病和衰老的基线。
