Mouse-Hamster Chimeric Prion Protein (PrP) Devoid of N-Terminal Residues 23-88 Restores Susceptibility to 22L Prions, but Not to RML Prions in PrP-Knockout Mice

Prion infection induces conformational conversion of the normal prion protein PrP C , into the pathogenic isoform PrP Sc , in prion diseases. It has been shown that PrP-knockout ( Prnp 0/0 ) mice transgenically reconstituted with a mouse-hamster chimeric PrP lacking N-terminal residues 23-88, or Tg(MHM2Δ23-88)/ Prnp 0/0 mice, neither developed the disease nor accumulated MHM2 Sc Δ23-88 in their brains after inoculation with RML prions. In contrast, RML-inoculated Tg(MHM2Δ23-88)/ Prnp 0/+ mice developed the disease with abundant accumulation of MHM2 Sc Δ23-88 in their brains. These results indicate that MHM2Δ23-88 itself might either lose or greatly reduce the converting capacity to MHM2 Sc Δ23-88, and that the co-expressing wild-type PrP C can stimulate the conversion of MHM2Δ23-88 to MHM2 Sc Δ23-88 in trans . In the present study, we confirmed that Tg(MHM2Δ23-88)/ Prnp 0/0 mice remained resistant to RML prions for up to 730 days after inoculation. However, we found that Tg(MHM2Δ23-88)/ Prnp 0/0 mice were susceptible to 22L prions, developing the disease with prolonged incubation times and accumulating MHM2 Sc Δ23-88 in their brains. We also found accelerated conversion of MHM2Δ23-88 into MHM2 Sc Δ23-88 in the brains of RML- and 22L-inoculated Tg(MHM2Δ23-88)/ Prnp 0/+ mice. However, wild-type PrP Sc accumulated less in the brains of these inoculated Tg(MHM2Δ23-88)/ Prnp 0/+ mice, compared with RML- and 22L-inoculated Prnp 0/+ mice. These results show that MHM2Δ23-88 itself can convert into MHM2 Sc Δ23-88 without the help of the trans -acting PrP C , and that, irrespective of prion strains inoculated, the co-expressing wild-type PrP C stimulates the conversion of MHM2Δ23-88 into MHM2 Sc Δ23-88, but to the contrary, the co-expressing MHM2Δ23-88 disturbs the conversion of wild-type PrP C into PrP Sc .