基于自噬溶酶体形成机制调控缺血性脑卒中后神经元自噬流

脑卒中是由脑血管阻塞或出血引发的急性脑血管病,约84%的临床脑卒中患者由脑缺血引起。研究表明,自噬广泛参与并显著影响脑卒中病理生理进程。自噬是一个将陈旧蛋白质、损伤细胞器及多余胞质组分等呈递给溶酶体进行降解的代谢过程,其包括自噬的激活、自噬体的形成和成熟、自噬体与溶酶体融合、自噬产物在自噬溶酶体内消化和降解等过程。自噬流通常被定义为自噬/溶酶体信号机制。最近发现,自噬流障碍是导致缺血性脑卒中后神经元损伤的重要原因,而在自噬过程中任一步骤发生障碍均可导致自噬流损伤。本文重点对自噬体-溶酶体融合的机制,以及该机制在缺血性脑卒中后发生障碍的致病机理进行详细阐述,以期基于自噬体-溶酶体融合机制对神经元自噬流进行调节,进而诱导缺血性脑卒中后的神经保护。本文可为脑卒中病理机制研究指明方向,为脑卒中治疗探寻新的线索。

Regulation of Autophagic Flux in Neurons Based on The Mechanism of Autolysosome Formation After Ischemic Stroke

Stroke is an acute cerebrovascular disease caused by cerebrovascular occlusion or hemorrhage, and approximately 84% of clinical stroke patients is suffered from cerebral ischemia (Ischemic stroke). Studies indicated that autophagy is extensively involved and prominently affects the pathophysiological development of stroke. Autophagy is a metabolic process by which delivers old proteins, damaged organelles and superfluous cytoplasmic components to lysosomes for degradation. It comprises a series of processes including activation of autophagy, formation and maturation of autophagosomes, fusion of autophagosomes with lysosomes, and digestion and degradation of autophagic substrates in autolysosomes. Autophagic flux is usually defined as autophagic/lysosomal signaling machinery. Recent studies reveal that dysfunction of autophagic flux is a critical pathogenesis of neuronal injury after ischemic stroke. However, disruption in any step in the autophagic/lysosomal pathway can lead to impairment of autophagic flux. This article is to be reviewed from the following four items. Firstly, excessive activation of autophagy, deficiency of autophagosome formation, fusion blockage of autophagosomes with lysosomes, as well as lysosomal inefficiency can drive dysfunction of autophagic flux and thereby aggravating neuronal injury. Secondly, fusion disruption between autophagosomes and lysosomes is an important cause of autophagic/lysosomal dysfunction in neurons. Consequently, a massive of autophagic substrates is accumulated within cells to worsen post-stroke damage. Thirdly, the fusion of autophagosomes with lysosomes is mainly mediated by the membrane-to-membrane fusion machinery via the three core elements: NSF (N-ethyl-maleimide sensitive factor ATPase), SNAP (soluble NSF attachment protein), and SNAREs (soluble NSF attachment protein receptors). SNAP is an adaptor attaching NSF to SNAREs, which are the proteins directly mediate the membrane fusion. After membrane-membrane fusion, SNAREs must be reactivated by NSF for the next round of fusion. It is vital that NSF is the sole ATPase to regenerate active SNAREs. SNF inactivation represses the reactivation of SNAREs and thereby disrupting the fusion between autophagosomes and lysosomes after ischemic stroke. Subsequently, the autophagic/lysosomal dysfunction in neurons is created to aggravate the neurological injury. Additionally, the insufficiency of the tethering proteins and inefficiency of the GTPases are also the pathologies to interrupt the fusion between autophagosomes and lysosomes. Accordingly, the impaired autophagic flux in neurons may be restored by facilitating fusion of autophagosomes with lysosomes, via pharmacological intervene, gene modulation, microenvironment amelioration, or mTOR signaling regulation. Finally, based on the mechanism of autolysosome formation, more therapeutic clues may be sought to alleviate neurological injury after ischemic stroke.