摘要
缺血性脑卒中是由脑血管梗塞引起的急性脑血管病,具有较高的发病率、致残率和致死率。研究发现,过度自噬或自噬不足均可导致细胞损伤。自噬包括自噬体的形成和成熟、自噬体与溶酶体融合、自噬底物在自噬溶酶体内的降解和清除,这些过程呈连续状态则称为自噬流。研究发现,脑缺血可导致自噬体与溶酶体间发生融合障碍,从而引发自噬流损伤。细胞内膜融合由3种核心组分介导,即N-乙基马来酰亚胺敏感因子(N-ethylmaleimide sensitive factor,NSF)ATP酶、可溶性NSF黏附蛋白(soluble NSF attachment protein,SNAP)及可溶性NSF黏附蛋白受体(soluble NSF attachment protein receptors,SNAREs)。当SNAREs介导自噬体与溶酶体融合后以非活性的复合体形式存留于自噬溶酶体膜,须被NSF再激活为单体后方可发挥新一轮的膜融合介导作用,而NSF是唯一可再激活SNAREs的ATP酶。新近研究表明,脑缺血可显著抑制NSF ATP酶活性,导致其对SNAREs再激活减少,这可能是自噬体与溶酶体间发生融合障碍并导致神经元自噬流损伤的病理机制。本文就NSF ATP酶失活导致SNAREs互作失调、自噬体与溶酶体融合障碍,以及蛋白水解酶向溶酶体的转运不足引发神经元自噬流障碍的病理机制进行阐述,并针对NSF ATP酶失活改善神经元自噬流的方法进行探讨,为提高脑卒中治疗提供参考并指明深入研究方向。
Cerebral ischemic stroke is an acute cerebrovascular disease caused by cerebral vascular occlusion,and it is associated with high incidence,disability,and mortality rates.Studies have found that excessive or insufficient autophagy can lead to cellular damage.Autophagy consists of autophagosome formation and maturation,autophagosome-lysosome fusion,degradation and clearance of autophagic substrates within autolysosomes,and these processes collectively constitute autophagic flux.Research has revealed that cerebral ischemia can induce impaired fusion between autophagosomes and lysosomes,resulting in autophagic flux impairment.Intracellular membrane fusion is mediated by three core components:N-ethylmaleimide sensitive factor(NSF)ATPase,soluble NSF attachment protein(SNAP),and soluble NSF attachment protein receptors(SNAREs).SNAREs,after mediating fusion between autophagosomes and lysosomes,remain in an inactive complex state on the autolysosomal membrane,requiring NSF reactivation into monomers to perform subsequent rounds of membrane fusion-mediated functions.NSF is the sole ATPase capable of reactivating SNAREs.Recent studies have shown that cerebral ischemia significantly inhibits NSF ATPase activity,reducing its reactivation of SNAREs.This may be a pathological mechanism for impaired fusion between autophagosomes and lysosomes,leading to neuronal autophagic flux impairment.This article discusses the pathological mechanisms of NSF ATPase inactivation,including SNAREs dysregulation,impaired fusion between autophagosomes and lysosomes,and insufficient transport of proteolytic enzymes to lysosomes,and explores approaches to improve neuronal autophagic flux through NSF ATPase reactivation.It provides references for stroke treatment improvement and points out directions for further research.
作者
雷倩
邓仪昊
何红云
LEI Qian;DENG Yi-Hao;HE Hong-Yun(Department of Human Anatomy,Faculty of Medicine,Kunming University of Science and Technology,Kunming 650500,China;Anning First People’s Hospital Affiliated to Kunming University of Science and Technology,Kunming 650399,China)
出处
《生物化学与生物物理进展》
SCIE
CAS
CSCD
北大核心
2024年第5期1034-1042,共9页
Progress In Biochemistry and Biophysics
基金
国家自然科学基金(82160240,82160241,81960418)
云南省“兴滇英才支持计划”青年项目(YNWR-QNBJ-2018-034)资助。
