Chen Liping, Jiang Huihui, Licinio Julio, Wu Haitao
Department of Neurobiology, Beijing Institute of Basic Medical Sciences, Beijing, 100850, China.
Department of Psychiatry, Norton College of Medicine, State University of New York, Upstate Medical University, Syracuse, NY, 13210, USA.
Mol Psychiatry. 2025 Jun;30(6):2754-2772. doi: 10.1038/s41380-025-02943-z. Epub 2025 Mar 3.
O-GlcNAcylation, a dynamic post-translational modification occurring on serine or threonine residues of numerous proteins, plays a pivotal role in various cellular processes, including gene regulation, metabolism, and stress response. Abundant in the brain, O-GlcNAcylation intricately governs neurodevelopment, synaptic assembly, and neuronal functions. Recent investigations have established a correlation between the dysregulation of brain O-GlcNAcylation and a broad spectrum of neurological disorders and injuries, spanning neurodevelopmental, neurodegenerative, and psychiatric conditions, as well as injuries to the central nervous system (CNS). Manipulating O-GlcNAcylation has demonstrated neuroprotective properties against these afflictions. This review delineates the roles and mechanisms of O-GlcNAcylation in the CNS under both physiological and pathological circumstances, with a focus on its neuroprotective effects in neurological disorders and injuries. We discuss the involvement of O-GlcNAcylation in key processes such as neurogenesis, synaptic plasticity, and energy metabolism, as well as its implications in conditions like Alzheimer's disease, Parkinson's disease, and ischemic stroke. Additionally, we explore prospective therapeutic approaches for CNS disorders and injuries by targeting O-GlcNAcylation, highlighting recent clinical developments and future research directions. This comprehensive overview aims to provide insights into the potential of O-GlcNAcylation as a therapeutic target and guide future investigations in this promising field.
O-连接的N-乙酰葡糖胺化（O-GlcNAcylation）是一种发生在众多蛋白质丝氨酸或苏氨酸残基上的动态翻译后修饰，在包括基因调控、代谢和应激反应在内的各种细胞过程中发挥着关键作用。O-GlcNAcylation在大脑中含量丰富，复杂地调控着神经发育、突触组装和神经元功能。最近的研究已经证实，大脑O-GlcNAcylation失调与广泛的神经系统疾病和损伤相关，涵盖神经发育、神经退行性和精神疾病，以及中枢神经系统（CNS）损伤。操纵O-GlcNAcylation已显示出对这些疾病的神经保护特性。本综述阐述了O-GlcNAcylation在生理和病理情况下在中枢神经系统中的作用和机制，重点关注其在神经系统疾病和损伤中的神经保护作用。我们讨论了O-GlcNAcylation在神经发生、突触可塑性和能量代谢等关键过程中的参与情况，以及其在阿尔茨海默病、帕金森病和缺血性中风等疾病中的意义。此外，我们探讨了通过靶向O-GlcNAcylation治疗中枢神经系统疾病和损伤的潜在方法，强调了最近的临床进展和未来的研究方向。这一全面概述旨在深入了解O-GlcNAcylation作为治疗靶点的潜力，并指导这一有前景领域的未来研究。
