Novel Role of HAX-1 in Neurons Protection After Spinal Cord Injury Involvement of IRE-1
Novel Role of HAX-1 in Neurons Protection After Spinal Cord Injury Involvement of IRE-1
复制标题
HAX-1 在脊髓损伤后神经元保护中的新作用 IRE-1 的参与
DOI：
10.1007/s11064-020-03088-x
复制
发表时间：
2020-07-17
影响因子：
4.4
通讯作者：
Song, Dianwen
中科院分区：
文献类型：
--
作者：
Chen, Jiajia;Yang, Saishuai;Song, Dianwen
脊髓损伤是人类致残率较高的疾病之一，目前尚无可靠的治疗方法。神经细胞凋亡是继发性损伤的重要组成部分，在脊髓损伤后神经功能障碍的发生发展中起重要作用。在本研究中，我们发现脊髓损伤后1d，HAX-1在神经元中的表达和分布增加。TUNEL实验证实，过表达HAX-1的PC12细胞凋亡减少，下调HAX-1后PC12细胞更容易发生凋亡。我们发现GRP94在脊髓组织和PC12细胞中表现出与HAX-1相同的表达趋势，并与HAX-1和IRE-1相互作用，这种相互作用在脊髓损伤后似乎得到加强。当HAX-1表达上调时，GRP94表达也增加，而IRE-1表达无明显变化。进一步的研究表明，HAX-1的过表达降低了IRE-1的表达，而不是IRE-1，并且IRE信号通路的下游蛋白(Caspase12、pJNK和CHOP)显著减少，反之亦然。HAX-1重组腺病毒治疗后，损伤脊髓组织中残留神经细胞较多，大鼠后肢运动功能明显改善。因此，我们推测HAX-1可能通过促进GRP94与IRE-1的解离来调节IRE-1信号通路，从而发挥保护脊髓损伤后神经元凋亡的作用。这可能为临床改善脊髓损伤后神经功能恢复提供理论依据和潜在的治疗靶点。
Spinal cord injury (SCI) is one of the diseases with high probability of causing disability in human beings, and there is no reliable treatment at present. Neuronal apoptosis is a vital component of secondary injury and plays a critical role in the development of neurological dysfunction after spinal cord injury. In this study, we found that the expression and distribution of HAX-1 in neurons increased 1 day after SCI. PC12 cells overexpressing HAX-1 showed decreased apoptosis and PC12 cells are more likely to undergo apoptosis after down-regulating HAX-1, which was confirmed via TUNEL experiments. We found GRP94 showed the same trend as HAX-1 in expression and interacted with HAX-1 and IRE-1 in both spinal cord tissue and PC12 cells, and this interaction seems to be enhanced after SCI. When the expression of HAX-1 was up-regulated, GRP94 also increased, but IRE-1 did not change at all. Further studies showed that overexpression of HAX-1 decreased the expression of pIRE-1, rather than IRE-1, and downstream proteins of the IRE signaling pathway (Caspase12, pJNK and CHOP) were significantly reduced, and vice versa. In animals treated with HAX-1 expressing adenovirus there are more neuronal cells remaining in the damaged spinal cord tissue, and hindlimb motor function of rats was significantly improved. So, we speculate that HAX-1 might play a role in protecting neurons from apoptosis after SCI by regulating the IRE-1 signaling pathway via promoting the dissociation of GRP94 from IRE-1. This may provide a theoretical basis and a potential therapeutic target for clinical improvement of neural function recovery after SCI.