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).