Abstract
Promoting axonal growth is essential for repairing damaged neuronal connections and motor function in spinal cord injury (SCI). Neuroleukin (NLK) exerts axonal growth activity in vitro and in vivo, but the mechanism remains unclear. This study reveals that the 78-kDa glucose-regulated protein (GRP78) is a NLK neuronal receptor that contributes to recovery from SCI. Binding and immunoprecipitation assays indicated that NLK binds to GRP78. Pretreatment to cultured neurons with a GRP78-neutralizing antibody suppressed NLK-induced axonal growth. Blocking cell surface GRP78 inhibited neuronal NLK-induced Akt activation. Treatment with an Akt inhibitor suppressed NLK-induced axonal growth. Continuous administration of NLK into the lateral ventricle of SCI mice increased axonal density in the injured region and restored motor function, which was not observed when NLK was simultaneously administered with a GRP78-neutralizing antibody. These results indicate that GRP78 regulates the NLK-induced axonal growth activity; NLK-GRP78 signaling promotes motor function recovery in SCI, presenting as a potential therapeutic target.
Highlights
Spinal cord injury (SCI) is caused by traumatic damage to the spinal cord and disruption of neuronal relays
The role of GRP78 as a cytosolic protein that belongs to the heat-shock protein family has been studied thoroughly (Casas, 2017), few studies have reported about the functions of GRP78 as a signal transduction receptor in cultured neurons (Goldenberg-Cohen et al, 2012; Bellani et al, 2014; Louessard et al, 2017)
Our study revealed NLK-GRP78 signaling as a new mechanism for the promotion of axonal growth and Akt was identified as a downstream molecule
Summary
Spinal cord injury (SCI) is caused by traumatic damage to the spinal cord and disruption of neuronal relays. The injured neuronal tracts are thought to rarely regrow, resulting in permanent impairment of motor, sensory, and autonomic function. A potentially effective strategy for recovery from these dysfunctions is the restoration of injured neuronal tracts by promoting axonal growth (Courtine and Sofroniew, 2019). Reactive astrocytes form the glial scar surrounding the lesion site and secrete chondroitin sulphate proteoglycans (CSPGs) that inhibit axonal growth (Silver and Miller, 2004; Bradbury and Burnside, 2019). Overcoming the inhibitory effects of CSPGs on axonal growth is important for accomplishing recovery from motor dysfunction. Neuroleukin (NLK) has been identified as a cytokine secreted from tumor cells (Liotta et al, 1986). Secreted NLK activates cell motility in an autocrine fashion in tumor cells (Silletti et al, 1991; Watanabe et al, 1991). NLK has been reported to show neurotrophic factor-like effects
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