Opposing Role of Prion Protein in Oxidative Stress- and ER Stress-induced Apoptotic Signaling

• Published in: Free radical biology & medicine Vol. 45; no. 11; pp. 1530 - 1541
• Main Authors: Anantharam, Vellareddy, Kanthasamy, Arthi, Choi, Christopher J, Martin, Dustin P, Latchoumycandane, Calivarathan, Richt, Jüergen A., Kanthasamy, Anumantha G.
• Format: Journal Article
• Language: English
• Published: 13.09.2008
• ISSN: 0891-5849
• DOI: 10.1016/j.freeradbiomed.2008.08.028

Although the prion protein is abundantly expressed in the CNS, its biological functions remain unclear. To determine the endogenous function of the cellular prion protein (PrP c ), we compared the effects of oxidative stress and endoplasmic reticulum (ER) stress inducers on apoptotic signaling in PrP c -expressing and PrP ko -knockout neural cells. H 2 O 2 , brefeldin-A (BFA) and tunicamycin (TUN) induced increases in caspase-9 and caspase-3, PKCδ proteolytic activation, and DNA fragmentation in PrP c and PrP ko cells. Interestingly, ER stress-induced activation of caspases, PKCδ, and apoptosis were significantly exacerbated in PrP c cells, whereas H 2 O 2 -induced proapoptotic changes were suppressed in PrP c compared to PrP ko cells. Additionally, caspases-12 and -8 were activated only in BFA and TUN treatments. Inhibitors of caspase-9, caspase-3, and PKCδ significantly blocked H 2 O 2 -, BFA- and TUN-induced apoptosis, whereas the caspase-8 inhibitor attenuated only BFA- and TUN-induced cell death, and the antioxidant MnTBAP blocked only H 2 O 2 -induced apoptosis. Overexpression of the kinase inactive PKCδ K376R or the cleavage site-resistant PKCδ D327A mutants suppressed both ER- and oxidative stress-induced apoptosis. Thus, PrP c plays a proapoptotic role during ER stress, and an anti-apoptotic role during oxidative stress-induced cell death. Together, these results suggest that cellular PrP c enhances the susceptibility of neural cells to impairment of protein processing and trafficking, but decreases the vulnerability to oxidative insults, and that PKCδ is a key downstream mediator of cellular stress-induced neuronal apoptosis.