Imbalance of antioxidant defense in mice lacking cellular prion protein.

Abstract Prion diseases are fatal neurodegenerative disorders resulting from conformational changes in the prion protein from its normal cellular isoform, PrP C , to the infectious scrapie isoform, PrP Sc . In spite of many studies, the physiological function of PrP C remains unknown. Recent work shows that PrP C binds Cu 2+ , internalizing it into the cytoplasm. Since many antioxidant enzymes depend on Cu 2+ (e.g., Cu/ZnSOD), their function could be affected in prion diseases. Here we investigate a possible relationship between PrP C and the cellular antioxidant systems in different structures isolated from PrP C knockout and wild-type mice by determining oxidative damage in protein and lipids and activity of antioxidant enzymes (CAT, SOD) and stress-adaptive enzymes (ODC). Our results show that, in the absence of PrP C , there is an increased oxidation of lipid and protein in all structures investigated. Decreased SOD activity and changes in CAT/ODC activities were also observed. Taking into account these results, we suggest that the physiological function of PrP C is related to cellular antioxidant defenses. Therefore, during development of prion diseases, the whole organism becomes more sensitive to ROS injury, leading to a progressive oxidative disruption of tissues and vital organs, especially the central nervous system.