title: 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.
abstract: Prion infection induces conformational conversion of the normal prion protein PrPC, into the pathogenic isoform PrPSc, in prion diseases. It has been shown that PrP-knockout (Prnp0/0) 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 MHM2ScΔ23-88 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 MHM2ScΔ23-88 in their brains. These results indicate that MHM2Δ23-88 itself might either lose or greatly reduce the converting capacity to MHM2ScΔ23-88, and that the co-expressing wild-type PrPC can stimulate the conversion of MHM2Δ23-88 to MHM2ScΔ23-88 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 MHM2ScΔ23-88 in their brains. We also found accelerated conversion of MHM2Δ23-88 into MHM2ScΔ23-88 in the brains of RML- and 22L-inoculated Tg(MHM2Δ23-88)/Prnp 0/+ mice. However, wild-type PrPSc 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 MHM2ScΔ23-88 without the help of the trans-acting PrPC, and that, irrespective of prion strains inoculated, the co-expressing wild-type PrPC stimulates the conversion of MHM2Δ23-88 into MHM2ScΔ23-88, but to the contrary, the co-expressing MHM2Δ23-88 disturbs the conversion of wild-type PrPC into PrPSc.
authors.affiliation: Division of Molecular Neurobiology, The Institute for Enzyme Research (KOSOKEN), The University of Tokushima, Kuramato, Tokushima, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Uchiyama
authors.affiliation: Animal Research Center, School of Medicine, University of Occupational and Environmental Health, Yahatanishi, Kitakyushu, Japan.
authors.forename: Hironori
authors.initials: H
authors.lastname: Miyata
authors.affiliation: Division of Molecular Neurobiology, The Institute for Enzyme Research (KOSOKEN), The University of Tokushima, Kuramato, Tokushima, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Yano
authors.affiliation: Division of Molecular Neurobiology, The Institute for Enzyme Research (KOSOKEN), The University of Tokushima, Kuramato, Tokushima, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Yamaguchi
authors.affiliation: Influenza and Prion Disease Research Center, National Institute of Animal Health, Tsukuba, Ibaraki, Japan.
authors.forename: Morikazu
authors.initials: M
authors.lastname: Imamura
authors.affiliation: Division of Molecular Neurobiology, The Institute for Enzyme Research (KOSOKEN), The University of Tokushima, Kuramato, Tokushima, Japan.
authors.forename: Naomi
authors.initials: N
authors.lastname: Muramatsu
authors.affiliation: Division of Molecular Neurobiology, The Institute for Enzyme Research (KOSOKEN), The University of Tokushima, Kuramato, Tokushima, Japan.
authors.forename: Nandita Rani
authors.initials: NR
authors.lastname: Das
authors.affiliation: Division of Molecular Neurobiology, The Institute for Enzyme Research (KOSOKEN), The University of Tokushima, Kuramato, Tokushima, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Chida
authors.affiliation: Division of Molecular Neurobiology, The Institute for Enzyme Research (KOSOKEN), The University of Tokushima, Kuramato, Tokushima, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Hara
authors.affiliation: Division of Molecular Neurobiology, The Institute for Enzyme Research (KOSOKEN), The University of Tokushima, Kuramato, Tokushima, Japan.
authors.forename: Suehiro
authors.initials: S
authors.lastname: Sakaguchi
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D006224:Cricetinae; D004198:Disease Susceptibility; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017096:Prion Diseases / Q000235:genetics / Q000378:metabolism*; D000072002:Prion Proteins; D011328:Prions / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*
chemical_list: D000072002:Prion Proteins; D011328:Prions; C512657:Prnp protein, mouse; D011993:Recombinant Fusion Proteins