JVI Accepts, published online ahead of print on 29 August 2007

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J. Virol. doi:10.1128/JVI.01434-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Mouse-adapted ovine scrapie prion strains are characterized by different conformers of PrPSc

Alana M. Thackray, Lee Hopkins, Michael A. Klein, and Raymond Bujdoso^*

Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge, UK, CB3 OES; Institute of Virology and Immunobiology, University of Würzburg, Versbacherstrasse 7, D-97078 Würzburg, Germany

^* To whom correspondence should be addressed. Email: rb202{at}cam.ac.uk.

The agent responsible for prion disease may exist in different forms, commonly referred to as strains, each carrying the specific information that determines their own distinct biological properties such as incubation period and lesion profile. Biological strain typing ovine scrapie isolates by serial passage in conventional mice has reported some diversity of ovine prion strains. However, this biological diversity remains poorly supported by biochemical prion strain typing. The protein-only hypothesis predicts that variation between different prion strains in the same host is manifest in different conformations adopted by PrPSc. Here we have investigated the molecular properties of PrPSc associated with two principal Prnp^a mouse-adapted ovine scrapie strains, namely RML and ME7, in order to establish biochemical prion strain typing strategies that may subsequently be used to discriminate field cases of mouse-passaged ovine scrapie isolates. We have used a conformation-dependent immunoassay and a conformational stability assay, together with western blot analysis, to demonstrate that RML and ME7 PrPSc show distinct biochemical and physicochemical properties. Although RML and ME7 PrPSc showed a similar resistance to proteolytic digestion, they differed in their glycoform profile and levels of PK-sensitive and PK-resistant isoforms. In addition, the PK-resistant core (PrP27-30) of ME7 was conformationally more stable following exposure to guanidine hydrochloride or sarkosyl than was RML PrP27-30. Our data show that mouse-adapted ovine scrapie strains can be discriminated by their distinct conformers of PrPSc, which provides a basis to investigate their diversity at the molecular level.

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