Lim Chong Teik, Lim Cheng Wei, Huang Tan, Ismail Elysha Nur, Reisi Parham, Cheah Pike See, Ling King Hwa
Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Selangor, Malaysia.
Department of Human Anatomy, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Selangor, Malaysia.
J Neurochem. 2025 Jun;169(6):e70132. doi: 10.1111/jnc.70132.
The synaptic system is the core of the nervous system, coordinating neural communication. Synaptic dysfunctions, including deficits in synaptogenesis, neurotransmission and plasticity, underlie various neurological diseases. Repressor element-1 silencing transcription factor (REST), an epigenetic transcription factor, plays a crucial role in neurodevelopment and neuroprotection by fine-tuning the expression of neuronal genes. REST binds to the RE-1 motif on target genes and recruits cofactors to exert transcriptional regulation. Dysregulation of REST, affecting thousands of downstream neuronal genes, is characteristic of neurological diseases with synaptic dysfunctions, including Huntington's disease, Alzheimer's disease, epilepsy, cerebral ischaemia, bipolar disorder and Kleefstra syndrome. Research on REST-targeted synaptic genes has been ongoing since 1993, using various fundamental and disease neuronal models. However, there has been no comprehensive review to consolidate the scattered knowledge of the regulatory role of REST in the synaptic system. Therefore, we reviewed and identified a list of REST-targeted and -regulated synaptic genes to address this gap. We found that REST plays significant roles in synapse development and function, particularly in the synaptic vesicle cycle, chemical neurotransmission systems and homeostasis of synaptic plasticity. Importantly, approaches to restore REST level in various neurological diseases have successfully rescued REST-targeted synaptic gene expression and ameliorated their synaptic and neuronal functions. This review serves as a foundation for future research on REST and neurological diseases. It aims to delineate the regulatory role of REST in the synaptic system and explore the potential of targeting REST restoration to improve synaptic functions in various neurological conditions.
突触系统是神经系统的核心，协调神经通讯。突触功能障碍，包括突触发生、神经传递和可塑性方面的缺陷，是各种神经疾病的基础。阻遏元件-1沉默转录因子（REST）是一种表观遗传转录因子，通过微调神经元基因的表达在神经发育和神经保护中发挥关键作用。REST与靶基因上的RE-1基序结合并募集辅因子以发挥转录调控作用。REST失调会影响数千个下游神经元基因，这是包括亨廷顿舞蹈病、阿尔茨海默病、癫痫、脑缺血、双相情感障碍和克莱夫斯特拉综合征在内的具有突触功能障碍的神经疾病的特征。自1993年以来，一直在使用各种基础和疾病神经元模型对REST靶向的突触基因进行研究。然而，尚未有全面的综述来整合关于REST在突触系统中调控作用的零散知识。因此，我们进行了综述并确定了一份REST靶向和调控的突触基因清单，以填补这一空白。我们发现REST在突触发育和功能中发挥着重要作用，特别是在突触小泡循环、化学神经传递系统和突触可塑性的稳态方面。重要的是，在各种神经疾病中恢复REST水平的方法已成功挽救了REST靶向的突触基因表达，并改善了它们的突触和神经元功能。本综述为未来关于REST和神经疾病的研究奠定了基础。其目的是阐明REST在突触系统中的调控作用，并探索靶向REST恢复以改善各种神经疾病中突触功能的潜力。
