Chronic wasting disease of elk and deer and Creutzfeldt-Jakob disease: Comparative analysis of the scrapie prion protein

Chronic wasting disease (CWD), a transmissible prion disease that affects elk and deer, poses new challenges to animal and human health. Although the transmission of CWD to humans has not been proven, it remains a possibility. If this were to occur, it is important to know whether the "acquired" human prion disease would show a phenotype including the scrapie prion protein (PrP^Sc) features that differ from those associated with human sporadic prion disease. In this study, we have compared the pathological profiles and PrP^Sc characteristics in brains of CWD-affected elk and deer with those in subjects with sporadic Creutzfeldt-Jakob disease (CJD), as well as CJD-affected subjects who might have been exposed to CWD, using histopathology, immunohistochemistry, immunoblotting, conformation stability assay, and N-terminal protein sequencing. Spongiform changes and intense PrP^Sc staining were present in several brain regions of CWD-affected animals. Immunoblotting revealed three proteinase K (PK)-resistant bands in CWD, representing different glycoforms of PrP^Sc. The unglycosylated PK-resistant PrP^Sc of CWD migrated at 21 kDa with an electrophoretic mobility similar to that of type 1 human PrP^Sc present in sporadic CJD affecting subjects homozygous for methionine at codon 129 (sCJDMM1). N-terminal sequencing showed that the PK cleavage site of PrP^Sc in CWD occurred at residues 82 and 78, similar to that of PrP^Sc in sCJDMM1. Conformation stability assay also showed no significant difference between elk CWD PrP^Sc and the PrP^Sc species associated with sCJDMM1. However, there was a major difference in glycoform ratio of PrP^Sc between CWD and sCJDMM1 affecting both subjects potentially exposed to CWD and non-exposed subjects. Moreover, PrP^Sc of CWD exhibited a distinct constellation of glycoforms distinguishable from that of sCJDMM1 in two-dimensional immunoblots. These findings underline the importance of detailed PrP^Sc characterization in trying to detect novel forms of acquired prion disease.