Laboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
J Mol Biol. 2012 Aug 10;421(2-3):204-36. doi: 10.1016/j.jmb.2012.01.051. Epub 2012 Feb 14.
It has been more than a century since the first evidence linking the process of amyloid formation to the pathogenesis of Alzheimer's disease. During the last three decades in particular, increasing evidence from various sources (pathology, genetics, cell culture studies, biochemistry, and biophysics) continues to point to a central role for the pathogenesis of several incurable neurodegenerative and systemic diseases. This is in part driven by our improved understanding of the molecular mechanisms of protein misfolding and aggregation and the structural properties of the different aggregates in the amyloid pathway and the emergence of new tools and experimental approaches that permit better characterization of amyloid formation in vivo. Despite these advances, detailed mechanistic understanding of protein aggregation and amyloid formation in vitro and in vivo presents several challenges that remain to be addressed and several fundamental questions about the molecular and structural determinants of amyloid formation and toxicity and the mechanisms of amyloid-induced toxicity remain unanswered. To address this knowledge gap and technical challenges, there is a critical need for developing novel tools and experimental approaches that will not only permit the detection and monitoring of molecular events that underlie this process but also allow for the manipulation of these events in a spatial and temporal fashion both in and out of the cell. This review is primarily dedicated in highlighting recent results that illustrate how advances in chemistry and chemical biology have been and can be used to address some of the questions and technical challenges mentioned above. We believe that combining recent advances in the development of new fluorescent probes, imaging tools that enabled the visualization and tracking of molecular events with advances in organic synthesis, and novel approaches for protein synthesis and engineering provide unique opportunities to gain a molecular-level understanding of the process of amyloid formation. We hope that this review will stimulate further research in this area and catalyze increased collaboration at the interface of chemistry and biology to decipher the mechanisms and roles of protein folding, misfolding, and aggregation in health and disease.
自首次将淀粉样蛋白形成过程与阿尔茨海默病发病机制联系起来以来，已经过去了一个多世纪。特别是在过去的三十年中，来自不同来源（病理学、遗传学、细胞培养研究、生物化学和生物物理学）的越来越多的证据不断指向几种无法治愈的神经退行性和全身性疾病发病机制的核心作用。这在一定程度上是由于我们对蛋白质错误折叠和聚集的分子机制以及淀粉样蛋白途径中不同聚集物的结构特性的理解的提高，以及新工具和实验方法的出现，这些方法允许更好地在体内对淀粉样蛋白形成进行特征描述。尽管取得了这些进展，但在体外和体内对蛋白质聚集和淀粉样蛋白形成的详细机制理解仍然存在一些挑战有待解决，并且关于淀粉样蛋白形成和毒性的分子和结构决定因素以及淀粉样蛋白诱导毒性的机制的几个基本问题仍然没有答案。为了弥补这一知识差距并应对技术挑战，迫切需要开发新的工具和实验方法，这些方法不仅可以检测和监测构成这一过程的分子事件，而且还可以在细胞内外以时空方式操纵这些事件。这篇综述主要致力于突出最近的研究结果，这些结果说明了化学和化学生物学的进步如何以及可以用来解决上述部分问题和技术挑战。我们相信，将新荧光探针的发展、能够可视化和追踪分子事件的成像工具以及蛋白质合成和工程的新方法方面的最新进展相结合，为获得淀粉样蛋白形成过程的分子水平理解提供了独特的机会。我们希望这篇综述将激发该领域的进一步研究，并促进化学和生物学界面的合作增加，以破译蛋白质折叠、错误折叠和聚集在健康和疾病中的机制和作用。
