p58^IPK Is an Endogenous Neuroprotectant for Retinal Ganglion Cells

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.