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Synergistic and strain-specific effects of bovine spongiform encephalopathy and scrapie prions in the cell-free conversion of recombinant prion protein

¹ Institute for Novel and Emerging Infectious Diseases at the Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, Boddenblick 5a, 17493 Greifswald-Insel Riems, Germany
² Institute for Chemistry and Biochemistry, Ernst-Moritz-Arndt-Universität, Greifswald, Germany
³ alicon AG, Wagistrasse 23, CH-8952 Schlieren, Switzerland

Correspondence
Martin H. Groschup
martin.groschup{at}fli.bund.de

This study describes the conversion of murine PrP^C by PrP^Sc from three different mouse scrapie strains (ME7, 87V and 22A) and from a mouse-passaged bovine spongiform encephalopathy (BSE) strain (BSE/Bl6). This was demonstrated by a modified, non-radioactive, cell-free conversion assay using bacterial prion protein, which was converted into a proteinase K (PK)-resistant fragment designated PrP^res. Using this assay, newly formed PrP^res could be detected by an antibody that discriminated de novo PrP^res and the original PrP^Sc seed. The results suggested that PrP^res formation occurs in three phases: the first 48 h when PrP^res formation is delayed, followed by a period of substantially accelerated PrP^res formation and a plateau phase when a maximum concentration of PrP^res is reached after 72 h. The conversion of prokaryotically expressed PrP^C by ME7 and BSE prions led to unglycosylated, PK-digested, abnormal PrP^res fragments, which differed in molecular mass by 1 kDa. Therefore, prion strain phenotypes were retained in the cell-free conversion, even when recombinant PrP^C was used as the substrate. Moreover, co-incubation of ME7 and BSE prions resulted in equal amounts of both ME7- and BSE-derived PrP^res fragments (as distinguished by their different molecular sizes) and also in a significantly increased total amount of de novo-generated PrP^res. This was found to be more than twice the amount of either strain when incubated separately. This result indicates a synergistic effect of both strains during cell-free conversion. It is not yet known whether such a cooperative action between BSE and scrapie prions also occurs in vivo.