Prothymosin-α plays a defensive role in retinal ischemia through necrosis and apoptosis inhibition

Abstract

Prothymosin-a (ProTa) causes a switch in cell death mode from necrosis to neurotrophin-reversible apoptosis in primary cultured cortical neurons. In the present study, post-ischemic administration (3 or 24 h, intravenously) of recombinant mouse ProTa without neurotrophins completely prevented ischemia-induced retinal damage accompanying necrosis and apoptosis, as well as dysfunction assessed by electroretinogram. Treatments with anti-erythropoietin (EPO) or brain-derived neurotrophic factor (BDNF) immunoglobulin G (IgG) reversed ProTa-induced inhibition of apoptosis. ProTa upregulated retinal EPO and BDNF levels in the presence of ischemia. Moreover, intravitreous administration of anti-ProTa IgG or an antisense oligodeoxynucleotide for ProTa accelerated ischemia-induced retinal damage. We also observed that ischemia treatment caused a depletion of ProTa from retinal cells. Altogether, these results suggest that the systemic administration of ProTa switches ischemia-induced necrosis to apoptosis, which in turn is inhibited by neurotrophic factors upregulated by ProTa and ischemia. ProTa released upon ischemic stress was found to have a defensive role in retinal ischemia.

Stress-induced non-vesicular release of prothymosin-α initiated by an interaction with S100A13, and its blockade by caspase-3 cleavage

“…the retinal ischemia model, the ischemic stress depletes ProTa from the retinal cells, and the intravitreous pretreatments with anti-ProTa IgG or antisense oligodeoxynucleotide against ProTa deteriorated the ischemic damage. 7 Therefore, it is evident that ProTa is extracellularly released from nuclei on ischemic stress, and that it exerts endogenous neuroprotective functions.…”

“…Indeed, this speculation was confirmed by in vivo study, in which exogenous ProTa inhibited both necrosis and apoptosis of retinal cells after ischemia, but the further treatment with anti-BDNF antibody disclosed the apoptosis induction by ProTa. 7 It should be noted that ProTa in the cytosol inhibits apoptosis through an inhibition of apoptosome formation in non-neuronal HeLa cells. 4 Furthermore, there is a report that ProTa is released from the nuclei when the NLS is cleaved off by caspase-3.…”

“…6,7 This protein is extracellularly released on starving or ischemic stress, and inhibits necrosis by inducing the membrane translocation of glucose transporters, which are endocytosed under ischemic conditions, resulting in an acceleration of necrosis owing to energy crisis. 5 On the basis of pharmacological analyses, ProTainduced translocation of glucose transporters is mediated by stimulation of a putative G i/o -coupled receptor, phospholipase C, and protein kinase C (PKC) b II .…”

Prothymosin-α Interacts with Mutant Huntingtin and Suppresses Its Cytotoxicity in Cell Culture

“…Previous in vitro studies have shown that ProT␣ is capable of preventing apoptotic cell death by inhibiting the formation of the apoptosome, a large cytosolic macromolecular complex formed in cells committed to programmed death (10). Recent in vivo studies have also revealed that ProT␣ not only inhibits apoptotic cell death but also suppresses necrotic cell death following ischemic stroke (17,18). In this report, using cell culture models of HD, we demonstrate that ProT␣ interacts with mHtt and reduces mHtt-caused cytotoxicity.…”

“…Because necrotic cell death is an overwhelming pathway by which cells die under specific cell culture condition, the overall effect of ProT␣ should still be protective (18). In ischemic stroke mouse studies, administration of purified ProT␣ remarkably inhibited both necrotic and apoptotic cell death (18).…”