Technical Abstract: The transmissible spongiform encephalopathies or prion diseases are a heterogeneous group of disorders associated with, and possibly caused by, accumulation of a neurotoxic, misfolded isoform, termed PrP-d, of a normal cellular protein, PrP-c. Primary amino acid differences and secondary conformational differences between the PrP-c of different species tends to limit the potential for interspecies transmission of these diseases. The notable exception is bovine spongiform encephalopathy, which as been causally linked to a newly described variant of the human prion diseas Creutzfeldt Jakob disease. In the United States, a prion disease of deer and elk, chronic wasting disease, is highly transmissible within the host species. PrP-d is relatively resistant to digestion with proteinase K and the cleavage site in the amino terminus is one of the criteria used to classify human prion disease. In addition, the relative abundance of unglycosylated, monoglycosylated and diglycosylated isoforms are evaluated. To estimate the potential for transmission of chronic wasting disease to human, the investigators compared the proteinase cleavage site and the relative abundance of each of the glycosylated isoforms of PrP-d from elk with chronic wasting disease and samples from humans with one form of sporadic Creutzfeldt Jakob disease. The study demonstrated that although the proteinase K cleavage sites were similar, there is a major difference in the glycoform ratio between the elk and the human samples, and that the elk disease exhibited a unique distribution of proteinase-resistant protein fragments when assayed on two dimensional gels. The study emphasizes the need to use several assays when comparing PrP-d molecules to assess the potential for interspecies transmission.