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Chronic wasting disease (CWD), a transmissible prion disease that affects elk and deer, poses new challenges to animal and human health. Although the transmission ofCWDto 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 (PrPSc) features that differ from those associated with human sporadic prion disease. In this study, we have compared the pathological profiles and PrPSc 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 PrPSc 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 PrPSc. The unglycosylated PK-resistant PrPSc ofCWDmigrated at 21 kDa with an electrophoretic mobility similar to that of type 1 human PrPSc present in sporadic CJD affecting subjects homozygous for methionine at codon 129 (sCJDMM1). N-terminal sequencing showed that the PK cleavage site of PrPSc in CWD occurred at residues 82 and 78, similar to that of PrPSc in sCJDMM1. Conformation stability assay also showed no significant difference between elkCWDPrPSc and the PrPSc species associated with sCJDMM1. However, there was a major difference in glycoform ratio of PrPSc between CWD and sCJDMM1 affecting both subjects potentially exposed to CWD and non-exposed subjects. Moreover, PrPSc of CWD exhibited a distinct constellation of glycoforms distinguishable from that of sCJDMM1 in two-dimensional immunoblots. These findings underline the importance of detailed PrPSc characterization in trying to detect novel forms of acquired prion disease.