p58IPK Is an Endogenous Neuroprotectant for Retinal Ganglion Cells

Abstract

p58IPK is an endoplasmic reticulum (ER)-resident chaperone playing a critical role in facilitating protein folding and protein homeostasis. Previously, we have demonstrated that p58IPK is expressed broadly in retinal neurons including retinal ganglion cells (RGCs) and loss of p58IPK results in age-related RGC degeneration. In the present study, we investigate the role of p58IPK 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, p58IPK −/− mice exhibit significantly increased RGC loss compared to wild type (WT) mice. In vitro, p58IPK-deficient RGCs show reduced viability and are more susceptible to cell death induced by the ER stress inducer tunicamycin (TM). Overexpression of p58IPK by adeno-associated virus (AAV) significantly diminishes TM-induced cell death in both WT and p58IPK −/− RGCs. Interestingly, we find that loss of p58IPK 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 p58IPK functions as an endogenous neuroprotectant for RGCs. The mechanisms underlying p58IPK’s neuroprotective action and the potential interactions between p58IPK and MANF warrant future investigation.

The Nrf2 activator MIND4‐17 protects retinal ganglion cells from high glucose‐induced oxidative injury

“…Non-adherent cells were incubated with mouse Thy-1.2 antibody (BD Biosciences) to isolate ganglion cells (McLaughlin, Dhimal, Li, Wang, & Zhang, 2018). The primary murine RGCs were seeded at a density of 3 × 10 5 cells per well.…”

Hepatocyte‐derived MANF alleviates hepatic ischaemia‐reperfusion injury via regulating endoplasmic reticulum stress‐induced apoptosis in mice

“…Therapeutic effects of MANF are mainly mentioned in Parkinson's disease, neurodegenerative diseases and cerebral stroke 12,14‐19 . Recently, more and more studies show that MANF not only affects neuron cells but also affects immune function, 20 hepatocellular carcinoma (HCC), 21 retinal development, 22 food intake and nephrotic syndrome 23 . Our previous study showed that MANF was extensively expressed in liver, and it was up‐regulated in para‐cancer tissue and down‐regulated in cancer tissues in HCC.…”

Novel insights into diabetes mellitus due to DNAJC3 ‐ defect: Evolution of neurological and endocrine phenotype in the pediatric age group

“…They showed increased P58 IPK expression during stress in WT mice, whereas stress enhanced apoptosis in retinal ganglion cells in the KO mice, suggesting a protective role of P58 IPK on retinal neurons during ER stress 29. McLaughlin et al recently showed that loss of p58 IPK led to reduced mRNA expression, but not the protein level, of mesencephalic astrocyte-derived neurotrophic factor (MANF), a neurotrophic factor that resides in the ER 30. Extensive investigation of nervous system in the animal model of DNAJC3 (P58 IPK ) KO is lacking.…”