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J. Biol. Chem., Vol. 281, Issue 7, 4199-4206, February 17, 2006

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Chronic Wasting Disease of Elk and Deer and Creutzfeldt-Jakob Disease

COMPARATIVE ANALYSIS OF THE SCRAPIE PRION PROTEIN^*

Zhiliang Xie, Katherine I. O'Rourke, Zhiqian Dong, Allen L. Jenny^¶, Julie A. Langenberg^||, Ermias D. Belay^**, Lawrence B. Schonberger^**, Robert B. Petersen, Wenquan Zou, Qingzhong Kong, Pierluigi Gambetti, and Shu G. Chen¹

From the Institute of Pathology and National Prion Disease Pathology Surveillance Center, Case Western Reserve University, Cleveland, Ohio 44106, United States Department of Agriculture Agricultural Research Services, Animal Disease Research Unit, Pullman, Washington 99164, ^¶United States Department of Agriculture National Veterinary Services Laboratories, Ames, Iowa 50010, ^||Wildlife Health Program, Bureau of Wildlife Management, Wisconsin Department of Natural Resources, Madison, Wisconsin 53707, and ^**National Center for Infectious Diseases, Division of Viral and Rickettsial Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia 30333

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.

Received for publication, August 16, 2005 , and in revised form, November 18, 2005.

^* This work was supported in part by United States Department of Agriculture Grant 2002-35201-12608 (to S. G. C.), Department of Defense Grant DAMD17-03-1-0283 (to S. G. C.), Centers for Disease Control and Prevention Contract UR8/CCU515004-01 (to P. G.), and National Institutes of Health Grant AG-14359 (to S. G. C. and P. G.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 216-368-8925; Fax: 216-368-2546; E-mail: shu.chen{at}case.edu.

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