eIF5A1/RhoGDIα pathway: a novel therapeutic target for treatment of spinal cord injury identified by a proteomics approach

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.

RhoA Inhibitor Treatment At Acute Phase of Spinal Cord Injury May Induce Neurite Outgrowth and Synaptogenesis

“…The MEMO1-RHOA-DIAPH1 signaling pathway plays an important role in ERBB2dependent stabilization of microtubules at the cell cortex and inhibits neurite outgrowth. Interestingly, a comparative proteomic approach performed by Liu et al (2015) (15) at the caudal segment level has shown that the eukaryotic translation initiation factor 5A1 (eIF5A1) and Rho GDP dissociation inhibitor alpha (RhoGDI␣), a member of Rho GDI family, played a major role in determining the extent of spontaneous functional recovery (15). In vitro, eIF5A1 overexpression in primary neurons increased cell survival and elongated neurite length whereas eIF5A1 knockdown reversed these effects (15).…”

Role of Nicotinamide N-Methyltransferase in Dorsal Striatum in Cocaine Place Preference

“…After binding to GTP, Rho GTPase family becomes activated Rho GTP; on the contrary, after binding to GDP, Rho GTPase family becomes inactivated Rho GDP (Jaffe and Hall, 2005;Tiedje et al, 2008). RhoGDIα blocks the dissociation of GDP from Rac1 and RhoA, making them inactive, which enhances the neurite growth, differentiation and neuroplasticity (Hancock and Hall, 1993;Liu et al, 2015). It is known that decreased methylation of Rac1 and RhoA increases their binding to RhoGDIα (Cushman and Casey, 2011).…”

“…As described previously (Liu et al, 2015;Shang et al, 2016), the protein was extracted by RIPA lysis buffer. Complete description of methods can be found in the Supplementary Methods.…”

“…On the contrary, after GTP is hydrolyzed to GDP, Rac1 and RhoA become inactivated (Jaffe and Hall, 2005;Tiedje et al, 2008). Rho GDP dissociation inhibitor α (RhoGDIα) blocks the dissociation of GDP from Rac1 and RhoA, making them inactive, which enhances the neurite growth, differentiation and neuroplasticity (Hancock and Hall, 1993;Liu et al, 2015).…”

“…Studies have shown that inhibition of LCMT significantly decreases the activation of both RhoA and Rac1, which is due to the increase in RhoGDIα binding by both proteins in the absence of their methylation (Cushman and Casey, 2011). Rac1 and RhoA are activated when they are methylated and bound to GTP, and function in inhibiting neurite growth (Bradke and Dotti, 2000;Liu et al, 2015). RhoGDIα blocks GDP's dissociation from methylated or unmethylated Rac1 and RhoA to keep them inactive, therefore promoting neurite growth (Bradke and Dotti, 2000).…”