SIRT1, a histone deacetylase, regulates prion protein-induced neuronal cell death

Prion diseases associated with the conversion of the cellular prion protein (PrP^C) to the misfolded isoform (PrP^Sc), affect the central nervous system (CNS) of humans and animals. Resveratrol, an activator of class III histone deacetylase SIRT1, is important in attenuating cellular injury and oxidative stress. The present study investigated the effects of SIRT1 activation on prion protein-mediated neuronal cell death and examined its possible signals in intracellular apoptotic pathways. Resveratrol treatment significantly increased both SIRT1 protein expression and SIRT1 activity and protected neuronal cells against PrP (106-126)-induced cell death. Resveratrol-mediated SIRT1 activation decreased the acetylation of p53 and p65 induced by prion protein and SIRT1 inhibitor. SIRT1 activation also inhibited PrP (106-126)-mediated p38 mitogen-activating protein kinase (MAPK) activation and caspase-3 cleavage, and increased the expression of anti-apoptotic Bcl-xL protein. Furthermore, SIRT1 overexpression by using adenoviral vector protected neuronal cells against PrP (106-126). These results indicate that resveratrol inhibits PrP (106-126)-induced neuronal cell death by regulating SIRT1 activity and SIRT-related signaling, and suggest that prion-related disease may be attenuated by SIRT1 activation or by intake of SIRT1-activating molecules.