Open AccessMouse-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
Author(s) -
Kimio Uchiyama,
Hironori Miyata,
Masashi Yano,
Yoshitaka Yamaguchi,
Morikazu Imamura,
Naomi Muramatsu,
Nandita Rani Das,
Junji Chida,
Hideyuki Hara,
Suehiro Sakaguchi
Publication year - 2014
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0109737
Subject(s) - hamster , gene isoform , inoculation , prion protein , knockout mouse , mesocricetus , microbiology and biotechnology , biology , incubation period , virology , incubation , chemistry , immunology , medicine , biochemistry , receptor , disease , gene
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 .