内质网应激的调节方式及其在脊髓损伤中的靶向作用

Regulation of Endoplasmic Reticulum Stress and Its Targeting Role in Spinal Cord Injury

内质网是维持细胞稳态的重要细胞器之一,主要参与细胞内脂质合成、蛋白质折叠以及钙离子稳态等过程。创伤、缺血和缺氧等一系列病理变化会使内质网内蛋白质的折叠功能发生障碍,引发内质网应激(endoplasmic reticulum stress,ERS)。脊髓损伤(spinal cord injury,SCI)是一种常见的创伤性疾病,致残率极高,严重影响生活质量,临床上至今没有安全有效的方法。已有大量数据表明,ERS是导致SCI后细胞死亡和神经元功能障碍的重要病理变化之一,并与SCI后神经元的凋亡、自噬和炎症等信号通路存在密切联系,但ERS与SCI之间的分子机制尚未研究透彻,合理认识和探索ERS与SCI相关的潜在分子机制,可能是未来SCI治疗取得重大突破的前提。本文首先归纳了ERS相关基因的变化与SCI病理过程之间的关系,然后从未折叠蛋白反应(unfolded protein response,UPR)、内质网相关降解(ER-associated degradation,ERAD)和内质网自噬(endoplasmic reticulophagy,ER-phagy)等3种主要调节方式入手,分析了ERS与SCI后细胞凋亡、炎症、自噬信号通路之间的相互关系,最后总结了近几年研究中靶向ERS治疗SCI的相关药物及应用前景,这可能为靶向ERS途径治疗SCI提供理论依据,并对未来SCI后治疗策略的开发提供一些思路和启示。

Endoplasmic reticulum is one of the most important organelles in maintaining cellular homeostasis,mainly involved in intracellular lipid synthesis,protein folding and calcium ion homeostasis.Trauma,ischemia and hypoxia and other pathological changes can cause protein folding dysfunction in the endoplasmic reticulum,triggering endoplasmic reticulum stress(ERS).Spinal cord injury(SCI)is a common traumatic disease with anextremely high disability rate,which seriously affects the quality of life.There is no safe and effective clinical methods so far.Investigations have shown that ERS is one of the important pathological changes leading to cell death and neuronal dysfunction after SCI,and is closely associated with signaling pathways such as apoptosis,autophagy,and inflammation in neurons after SCI;however,the molecular mechanisms between ERS and SCI have not yet been thoroughly investigated.A deeper understanding and exploration of the potential molecular mechanisms associated with ERS and SCI may be the future SCI therapeutics.In this paper,we first summarized the relationship between the changes of ERS-related genes and the pathological process of SCI,Then the interrelationships between ERS and the apoptosis,inflammation,and autophagy signaling pathways after SCI were analyzed,starting from the three main modes of regulation,including unfolded protein response(UPR),endoplasmic reticulum-associated degradation(ERAD),and endoplasmic reticulophagy(ER-phagy),Finally,we summarize the relevant drugs and application prospects of targeting ERS for SCI in recent years,which may provide a theoretical basis for targeting the ERS pathway for SCI and provide some ideas and insights for the development of future therapeutic strategies after SCI.