Departments of Chemistry, University of Southern California, Los Angeles, CA 90089, U.S.A.
Biological Sciences, University of Southern California, Los Angeles, CA 90089, U.S.A.
Biochem J. 2021 Jul 30;478(14):2733-2758. doi: 10.1042/BCJ20200609.
Neurodegenerative diseases such as Alzheimer's and Parkinson's remain highly prevalent and incurable disorders. A major challenge in fully understanding and combating the progression of these diseases is the complexity of the network of processes that lead to progressive neuronal dysfunction and death. An ideal therapeutic avenue is conceivably one that could address many if not all of these multiple misregulated mechanisms. Over the years, chemical intervention for the up-regulation of the endogenous posttranslational modification (PTM) O-GlcNAc has been proposed as a potential strategy to slow down the progression of neurodegeneration. Through the development and application of tools that allow dissection of the mechanistic roles of this PTM, there is now a growing body of evidence that O-GlcNAc influences a variety of important neurodegeneration-pertinent mechanisms, with an overall protective effect. As a PTM that is appended onto numerous proteins that participate in protein quality control and homeostasis, metabolism, bioenergetics, neuronal communication, inflammation, and programmed death, O-GlcNAc has demonstrated beneficence in animal models of neurodegenerative diseases, and its up-regulation is now being pursued in multiple clinical studies.
神经退行性疾病，如阿尔茨海默病和帕金森病，仍然是高度流行且无法治愈的疾病。充分理解和对抗这些疾病进展的主要挑战是导致进行性神经元功能障碍和死亡的过程网络的复杂性。一种理想的治疗途径可以说是一种可以解决许多甚至所有这些失调机制的方法。多年来，化学干预上调内源性翻译后修饰（PTM）O-GlcNAc 已被提议作为减缓神经退行性变进展的潜在策略。通过开发和应用允许剖析这种 PTM 的机制作用的工具，现在有越来越多的证据表明 O-GlcNAc 影响多种重要的与神经退行性变相关的机制，具有整体保护作用。作为一种附加到参与蛋白质质量控制和动态平衡、代谢、生物能量学、神经元通讯、炎症和程序性死亡的众多蛋白质上的 PTM，O-GlcNAc 在神经退行性疾病的动物模型中表现出益处，并且现在正在进行多项临床研究来上调其水平。
