GRP78-Mediated Signaling Contributes to Axonal Growth Resulting in Motor Function Recovery in Spinal Cord-Injured Mice

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 NLKinduced 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.

Glucose‐regulated protein (GRP78) is an important cell surface receptor for viral invasion, cancers, and neurological disorders

“…87 Furthermore, csGRP78 is also a receptor for neuroleukin that exerts axonal growth activity in vitro and in vivo, playing a key role in motor function recovery in spinal cord-injured mice. 90 Astrocytes also express csGRP78, 91 that may be involved in the control of the balance between plasmin formation and plasmin elimination in the brain parenchyma. 92 Astrocytes are particularly interesting because they become reactive in several neurodegenerative disorders including Parkinson's, Alzheimer's, Huntington's, and prion diseases.…”

“…Therefore, csGRP78 plays a dual role in mechanisms of neuroprotection by tPA, one by promoting its expression and secretion, and the other by serving as its receptor on the cell surface, where in association with tPA decreases ER stress and neuronal death during cerebral ischemia independently of tPA thrombolytic activity 87 . Furthermore, csGRP78 is also a receptor for neuroleukin that exerts axonal growth activity in vitro and in vivo, playing a key role in motor function recovery in spinal cord‐injured mice 90 . Astrocytes also express csGRP78, 91 that may be involved in the control of the balance between plasmin formation and plasmin elimination in the brain parenchyma 92 .…”

“…Astrocytes also express csGRP78, 91 that may be involved in the control of the balance between plasmin formation and plasmin elimination in the brain parenchyma 92 . Astrocytes are particularly interesting because they become reactive in several neurodegenerative disorders including Parkinson's, Alzheimer's, Huntington's, and prion diseases 90 . In all these disorders, activation of the UPR has been detected in brain tissue and specifically the PERK/eIF2α‐P pathway regulated by GRP78, 93 emphasizing the importance of neuronal expression of csGRP78.…”