Prion Protein Devoid of the Octapeptide Repeat Region Delays Bovine Spongiform Encephalopathy Pathogenesis in Mice

Conformational conversion of the cellular isoform of prion protein, PrP^C, into the abnormally folded, amyloidogenic isoform, PrP^Sc, is a key pathogenic event in prion diseases, including Creutzfeldt-Jakob disease in humans and scrapie and bovine spongiform encephalopathy (BSE) in animals. We previously reported that the octapeptide repeat (OR) region could be dispensable for converting PrP^C into PrP^Sc after infection with RML prions. We demonstrated that mice transgenically expressing mouse PrP with deletion of the OR region on the PrP knockout background, designated Tg(PrPΔOR)/Prnp^/ mice, did not show reduced susceptibility to RML scrapie prions, with abundant accumulation of PrP^ScΔOR in their brains. We show here that Tg(PrPΔOR)/Prnp^/ mice were highly resistant to BSE prions, developing the disease with markedly elongated incubation times after infection with BSE prions. The conversion of PrPΔOR into PrP^ScΔOR was markedly delayed in their brains. These results suggest that the OR region may have a crucial role in the conversion of PrP^C into PrP^Sc after infection with BSE prions. However, Tg(PrPΔOR)/Prnp^/ mice remained susceptible to RML and 22L scrapie prions, developing the disease without elongated incubation times after infection with RML and 22L prions. PrP^ScΔOR accumulated only slightly less in the brains of RML- or 22L-infected Tg(PrPΔOR)/Prnp^/ mice than PrP^Sc in control wild-type mice. Taken together, these results indicate that the OR region of PrP^C could play a differential role in the pathogenesis of BSE prions and RML or 22L scrapie prions.IMPORTANCE Structure-function relationship studies of PrP^C conformational conversion into PrP^Sc are worthwhile to understand the mechanism of the conversion of PrP^C into PrP^Sc We show here that, by inoculating Tg(PrPΔOR)/Prnp^/ mice with the three different strains of RML, 22L, and BSE prions, the OR region could play a differential role in the conversion of PrP^C into PrP^Sc after infection with RML or 22L scrapie prions and BSE prions. PrPΔOR was efficiently converted into PrP^ScΔOR after infection with RML and 22L prions. However, the conversion of PrPΔOR into PrP^ScΔOR was markedly delayed after infection with BSE prions. Further investigation into the role of the OR region in the conversion of PrP^C into PrP^Sc after infection with BSE prions might be helpful for understanding the pathogenesis of BSE prions.