Chronic Wasting Disease of Elk and Deer and Creutzfeldt-Jakob Disease COMPARATIVE ANALYSIS OF THE SCRAPIE PRION PROTEIN

Authors

Zhiliang Xie, Case Western Reserve University
Katherine I. O'Rourke, U.S. Department of AgricultureFollow
Zhiqian Dong, Case Western Reserve University
Allen L. Jenny, USDA National Veterinary Services Laboratories
Julie A. Langenberg, Wisconsin Department of Natural Resources
Ermais D. Belay, National Center for Infectious Diseases
Lawrence B. Schonberger, National Center for Infectious Diseases
Robert B. Petersen, Case Western Reserve University
Wenquan Zou, Case Western Reserve University
Quingzhong Kong, Case Western Reserve University
Pierluigi Gambetti, Case Western Reserve University
Shu G. Chen, Case Western Reserve UniversityFollow

Date of this Version

2006

Comments

Published in THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 281, NO. 7, pp. 4199–4206, February 17, 2006

Abstract

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 (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 ofCWDmigrated 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 elkCWDPrPSc 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.