Find in Library

p58^IPK is a multifaceted endoplasmic reticulum (ER) chaperone and a regulator of eIF2α kinases involved in a wide range of cellular processes including protein synthesis, ER stress response, and macrophage-mediated inflammation. Systemic deletion of p58^IPK leads to age-related loss of retinal ganglion cells (RGC) and exacerbates RGC damage induced by ischemia/reperfusion and increased intraocular pressure (IOP), suggesting a protective role of p58^IPK in the retina. However, the mechanisms remain elusive. Herein, we investigated the cellular mechanisms underlying the neuroprotection action of p58^IPK using conditional knockout (cKO) mouse lines where p58^IPK is deleted in retinal neurons (Chx10-p58^IPK cKO) or in myeloid cells (Lyz2-p58^IPK cKO). In addition, we overexpressed p58^IPK by adeno-associated virus (AAV) in the retina to examine the effect of p58^IPK on RGC survival after ocular hypertension (OHT) in wild type (WT) mice. Our results show that overexpression of p58^IPK by AAV significantly improved RGC survival after OHT in WT mice, suggesting a protective effect of p58^IPK on reducing RGC injury. Conditional knockout of p58^IPK in retinal neurons or in myeloid cells did not alter retinal structure or cellular composition. However, a significant reduction in the b wave of light-adapted electroretinogram (ERG) was observed in Chx10-p58^IPK cKO mice. Deletion of p58^IPK in retinal neurons exacerbates RGC loss at 14 days after OHT. In contrast, deficiency of p58^IPK in myeloid cells increased the microglia/macrophage activation but had no effect on RGC loss. We conclude that deletion of p58^IPK in macrophages increases their activation, but does not influence RGC survival. These results suggest that the neuroprotective action of p58^IPK is mediated by its expression in retinal neurons, but not in macrophages. Therefore, targeting p58^IPK specifically in retinal neurons is a promising approach for the treatment of neurodegenerative retinal diseases including glaucoma.