Novel Role of HAX-1 in Neurons Protection After Spinal Cord Injury Involvement of IRE-1
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ORIGINAL PAPER
Novel Role of HAX‑1 in Neurons Protection After Spinal Cord Injury Involvement of IRE‑1 Jiajia Chen1,2 · Saishuai Yang3 · Chunshuai Wu2 · Zhiming Cui2 · Yangyang Wan4 · Guanhua Xu2 · Guofeng Bao2 · Jinlong Zhang2 · Chu Chen2 · Dianwen Song1 Received: 25 February 2020 / Revised: 5 June 2020 / Accepted: 6 July 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract 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. Keywords Spinal cord injury · Neuron apoptosis · HAX-1 · GRP94 · IRE-1
Introduction
* Dianwen Song [email protected] 1
Department of Orthopedics, Shanghai General Hospital of Nanjing Medical University, 650 Xinsongjiang Road, Shanghai 201620, China
2
Department of Spine Surgery, The Second Affiliated Hospital of Nantong University, 6 Haier Lane North Road, Nantong 226001, Jiangsu, China
3
Department of Anesthesiology, The Second Affiliated Hospital of Nantong University, 6 Haier Lane North Road, Nantong 226001, Jiangsu, China
4
Department of Clinical Laboratory, The Second Affiliated Hospital of Nantong University, 6 Haier Lane North Road, Nantong 226001, Jiangsu, China
Spinal cord injury (SCI) is a common and serious disease with increasing morbidity and mortality, which often leads to physical, psychological and social barriers [1–3]. According to different mechanisms and timings associated with nerve damage, traumatic SCI is always divided into primary and secondary injur
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