EIF5A1/RhoGDIα pathway: a novel therapeutic target for treatment of spinal cord injury identified by a proteomics approach.

Wei Liu,Jin Liu,Ran Liu,Lei Xia,Chen-Yun Li,Visar Belegu,Fei-Fei Shang,Ting-Hua Wang,Wei Wang,Yang Xu,Wei Zhao

doi:10.1038/srep16911

Abstract

Spinal cord injury (SCI) is frequently accompanied by a degree of spontaneous functional recovery. The underlying mechanisms through which such recovery is generated remain elusive. In this study, we observed a significant spontaneous motor function recovery 14 to 28 days after spinal cord transection (SCT) in rats. Using a comparative proteomics approach, caudal to the injury, we detected difference in 20 proteins. Two of these proteins, are eukaryotic translation initiation factor 5A1 (eIF5A1) that is involved in cell survival and proliferation, and Rho GDP dissociation inhibitor alpha (RhoGDIα), a member of Rho GDI family that is involved in cytoskeletal reorganization. After confirming the changes in expression levels of these two proteins following SCT, we showed that in vivo eIF5A1 up-regulation and down-regulation significantly increased and decreased, respectively, motor function recovery. In vitro, eIF5A1 overexpression in primary neurons increased cell survival and elongated neurite length while eIF5A1 knockdown reversed these results. We found that RhoGDIα up-regulation and down-regulation rescues the effect of eIF5A1 down-regulation and up-regulation both in vivo and in vitro. Therefore, we have identified eIF5A1/RhoGDIα pathway as a new therapeutic target for treatment of spinal cord injured patients.

Highlights

Eukaryotic translation initiation factor, a protein containing the unusual amino acid hypusine, is highly expressed in neonatal brain[14,15,16], but its function in the central nervous system (CNS) remains elusive
A proteomics screen identified 20 proteins whose expression levels related to spontaneous functional recovery in spinal cord transection (SCT) rats
Axonal damage at the epicenter of pathologies such as stroke, traumatic brain injury (TBI) and Spinal cord injury (SCI) patients can result in signal conduction failure at the epicenter of their pathology due to which in turn causes persistent functional deficit

Summary

Introduction

Eukaryotic translation initiation factor (eIF5A1), a protein containing the unusual amino acid hypusine, is highly expressed in neonatal brain[14,15,16], but its function in the central nervous system (CNS) remains elusive. Actin and microtubule dynamics are obligatory downstream effectors of several signaling cascades involved in axonal elongation. Cytoskeletal regulators such as Rho GTPases and proteins that regulate their function can modulate neuronal plasticity by manipulating actin and microtubule dynamics[18,19,20,21]. Using a proteomics approach we identify eIF5A1 and RhoGDIα as proteins that are upregulated during rats’ spontaneous motor function recovery. Both of these proteins are in the same signaling pathway that leads to enhanced neuronal survival and axonal regeneration. The present findings indicate a new strategy to treat patients with SCI

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Conclusion