Hypoxia protects neuronal cells from human prion protein fragment‐induced apoptosis

Abstract

J. Neurochem. (2010) 112, 715–722. Abstract Prion diseases are neurodegenerative disorders characterized by the accumulation of an abnormal isoform of the prion protein PrPSc. Human prion protein fragment, PrP (106–126) (prion protein peptide 106–126), may contain most of the pathological features associated with PrPSc. Hypoxic conditions elicit cellular responses adaptively designed to improve cell survival and have an important role in the process of cell survival. We investigate the effects of hypoxia on PrP (106–126)‐induced apoptosis in the present study. Human neuroblastoma and glioblastoma cells were incubated with varied doses of PrP (106–126) under both normoxic or hypoxic conditions, in order to determine the regulatory effects of hypoxia on PrP (106–126)‐induced apoptosis. The results indicate that hypoxia protects neuronal cells against PrP (106–126)‐induced cell death by activating the Akt signal, which is inactivated by prion proteins, and inhibiting PrP (106–126)‐induced caspase 3 activation. Low oxygen conditions increase the Bcl‐2 protein, which is associated with anti‐apoptotic signals, and recover the PrP (106–126)‐induced reduction in mitochondrial transmembrane potential. This study demonstrates that hypoxia inhibits PrP (106–126)‐induced neuron cell death by regulating Akt and Akt‐related signaling, and it also suggests that prion‐related neuronal damage and disease may be regulated by hypoxia or by hypoxic‐inducing genes.

Trafficking of PrPcto mitochondrial raft-like microdomains during cell apoptosis

“…32 In addition, the PrP Sc protein or PrP (106-126) induces neuronal cell death by increasing p53, p-ERK and p-p38 protein levels and decreasing bcl-2 protein levels. 33 Hachiya et al showed that transgenic mice harboring a high copy number of wild-type mouse PrP C developed a spontaneous neurological dysfunction, probably due to mitochondria-mediated neuronal apoptosis in aged transgenic mice overexpressing wild-type PrP C . The aged mice exhibited an aberrant mitochondrial localization of PrP C concomitant with decreased manganese superoxide dismutase activity, cytochrome c release, caspase-3 activation and DNA fragmentation, most predominantly in hippocampal neuronal cells.…”

Sulforaphane blocks hypoxia-mediated resistance to TRAIL-induced tumor cell death

“…cell lines were lysed in a lysis buffer (25 mM HePeS; pH 7.4, 100 mM nacl, 1 mM edTa, 5 mM Mgcl 2 , 0.1 mM dTT and protease inhibitor mixture). Proteins were electrophoretically resolved on an 8-15% SdS gel, and immunoblotting was performed as previously described (19). equal amounts of protein lysates were resolved on an 8-15% SdS-polyacrylamide gel and electrophoretically transferred to a nitrocellulose membrane.…”

Bee venom phospholipase A2 prevents prion peptide induced-cell death in neuronal cells

“…Although the mechanisms of PrPSc neurotoxicity are yet unclear, recent studies support the hypothesis that PrPSc induces neuronal cell death and activates caspase-3 through the p38-JNK mitogen-activated protein kinase (MAPK) pathway (2,11,12). Seo et al studying PrP peptide 106-126 [PrP(106-126)]-treated SH-SY5Y cells, have shown that PrP(106-126)-induced neurotoxicity is decreased by repression of p38 MAPK activation with exposure to the SIRT1 activator, resveratrol (13).…”