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J. Biol. Chem., Vol. 282, Issue 26, 18702-18710, June 29, 2007

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Scrapie Infection of Prion Protein-deficient Cell Line upon Ectopic Expression of Mutant Prion Proteins^*

Elke Maas, Markus Geissen¹, Martin H. Groschup, Romina Rost, Takashi Onodera^¶, Hermann Schätzl, and Ina M. Vorberg²

From the Institute of Virology, Technical University of Munich, Troger Strasse 30, 81675 Munich, Germany, Friedrich-Loeffler-Institut, Institute for Novel and Emerging Infectious Diseases, 17493 Greifswald-Insel Riems, Germany, and ^¶Department of Molecular Immunology, Graduate School of Agricultural and Life Sciences, University of Tokyo, Yayoi 1-1-1, Tokyo 113-8657, Japan

Expression of the cellular prion protein (PrP^C) is crucial for susceptibility to prions. In vivo, ectopic expression of PrP^C restores susceptibility to prions and transgenic mice that express heterologous PrP on a PrP knock-out background have been used extensively to study the role of PrP alterations for prion transmission and species barriers. Here we report that prion protein knock-out cells can be rendered permissive to scrapie infection by the ectopic expression of PrP. The system was used to study the influence of sheep PrP-specific residues in mouse PrP on the infection process with mouse adapted scrapie. These studies reveal several critical residues previously not associated with species barriers and demonstrate that amino acid residue alterations at positions known to have an impact on the susceptibility of sheep to sheep scrapie also drastically influence PrP^Sc formation by mouse-adapted scrapie strain 22L. Furthermore, our data suggest that amino acid polymorphisms located on the outer surfaces of helix 2 and 3 drastically impact conversion efficiency. In conclusion, this system allows for the fast generation of mutant PrP^Sc that is entirely composed of transgenic PrP and is, thus, ideally suited for testing if artificial PrP molecules can affect prion replication. Transmission of infectivity generated in HpL3-4 cells expressing altered PrP molecules to mice could also help to unravel the potential influence of mutant PrP^Sc on host cell tropism and strain characteristics in vivo.

Received for publication, February 14, 2007 , and in revised form, March 28, 2007.

^* This work was supported by Deutsche Forschungsgesellschaft Grants VO 1277/1-2 and SCHA 594/3-4, SFB 596 A8, and B14 and by European Commission Grant TSEUR LSHB-CT-2005-018805. This study was performed within the framework of EU FP6 Network of Excellence Neuroprion. 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 Present address: Institute of Neuropathology, UKE-Hamburg, 20246 Hamburg, Germany.

² To whom correspondence should be addressed. Tel.: 49-89-4140-6814; Fax: 49-89-4140-6823; E-mail: vorberg{at}lrz.tum.de.

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