Abstract
p58(IPK) is an endoplasmic reticulum (ER)-resident chaperone playing a critical role in facilitating protein folding and protein homeostasis. Previously, we have demonstrated that p58(IPK) is expressed broadly in retinal neurons including retinal ganglion cells (RGCs) and loss of p58(IPK) results in age-related RGC degeneration. In the present study, we investigate the role of p58(IPK) in neuroprotection by in vitro and in vivo studies using primary RGC culture and two well-established disease-relevant RGC injury models: retinal ischemia/reperfusion (I/R) and microbead-induced ocular hypertension. Our results demonstrate that in both in vivo models, p58(IPK -/-) mice exhibit significantly increased RGC loss compared to wild type (WT) mice. In vitro, p58(IPK)-deficient RGCs show reduced viability and are more susceptible to cell death induced by the ER stress inducer tunicamycin (TM). Overexpression of p58(IPK) by adeno-associated virus (AAV) significantly diminishes TM-induced cell death in both WT and p58(IPK -/-) RGCs. Interestingly, we find that loss of p58(IPK) leads to reduced mRNA expression, but not the protein level, of mesencephalic astrocyte-derived neurotrophic factor (MANF), a neurotrophic factor that resides in the ER. Treatment with recombinant MANF protein protects R28 retinal neural cells and mouse retinal explants from TM-induced cell death. Taken together, our study suggests that p58(IPK) functions as an endogenous neuroprotectant for RGCs. The mechanisms underlying p58(IPK)'s neuroprotective action and the potential interactions between p58(IPK) and MANF warrant future investigation.