PrPSc Inhibition and Cellular Protection of DBL on a Prion-Infected Cultured Cell via Multiple Pathways.

Abstract

Prion diseases are kinds of fatal neurodegenerative diseases without effective therapeutic and prophylactic tools currently. In this study, the inhibition of PrPSc propagation and cellular protectivity of 3,4-dihydroxybenzalacetone (DBL), a small catechol-containing compound isolated and purified from the ethanol extract of Inonotus obliquus, upon a prion-infected cell line SMB-S15 were evaluated. Western blots showed that after incubation with 10μM of DBL for 14days, the level of PrPSc in SMB-S15 cells was significantly decreased. Meanwhile, the levels of ROS and hydrogen peroxide were decreased with a dose-dependent manner, whereas the levels of some antioxidant factors, such as HO-1, GCLC and GCLM, were significantly increased. The activities of total glutathione and SOD were up-regulated. DBL-treated SMB-S15 cells also showed the up-regulation of UPR-related proteins, including PERK, IRE1α, ATF6 and GRP78, and activation of autophagy system. Furthermore, the SIRT3 abnormalities caused by prion infection were relieved by DBL treatment. On the contrary, these comprehensive changes were not significantly noticed in the normal partner cell line SMB-PS under the same experimental condition. Those data indicate that treatment of DBL on prion-infected cells can reduce PrPSc level, activate UPR and autophagy system and meanwhile relieve intracellular oxidative stress, endoplasmic reticulum stress and mitochondrial dysfunction by raising the levels of multiple antioxidant factors. The PrPSc inhibition and protective effectiveness of DBL upon the prion-infected cells in vitro make it worthy of further study.