title: Effects of prion protein devoid of the N-terminal residues 25-50 on prion pathogenesis in mice.
abstract: The N-terminal polybasic region of the normal prion protein, PrPC, which encompasses residues 23-31, is important for prion pathogenesis by affecting conversion of PrPCinto the pathogenic isoform, PrPSc. We previously reported transgenic mice expressing PrP with residues 25-50 deleted in the PrP-null background, designated as Tg(PrP∆preOR)/Prnp0/0mice. Here, we produced two new lines of Tg(PrP∆preOR)/Prnp0/0mice, each expressing the mutant protein, PrP∆preOR, 1.1 and 1.6 times more than PrPCin wild-type mice, and subsequently intracerebrally inoculated RML and 22L prions into them. The lower expresser showed slightly reduced susceptibility to RML prions but not to 22L prions. The higher expresser exhibited enhanced susceptibility to both prions. No prion transmission barrier was created in Tg(PrP∆preOR)/Prnp0/0mice against full-length PrPSc. PrPSc∆preOR accumulated in the brains of infected Tg(PrP∆preOR)/Prnp0/0mice less than PrPScin control wild-type mice, although lower in RML-infected Tg(PrP∆preOR)/Prnp0/0mice than in 22L-infected mice. Prion infectivity in infected Tg(PrP∆preOR)/Prnp0/0mice was also lower than that in wild-type mice. These results indicate that deletion of residues 25-50 only slightly affects prion susceptibility, the conversion of PrPCinto PrPSc, and prion infectivity in a strain-specific way. PrP∆preOR retains residues 23-24 and lacks residues 25-31 in the polybasic region. It is thus conceivable that residues 23-24 rather than 25-31 are important for the polybasic region to support prion pathogenesis. However, other investigators have reported that residues 27-31 not 23-24 are important to support prion pathogenesis. Taken together, the polybasic region might support prion pathogenesis through multiple sites including residues 23-24 and 27-31.
authors.affiliation: Division of Molecular Neurobiology, Institute for Enzyme Research (KOSOKEN), Tokushima University, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan.
authors.forename: Nandita Rani
authors.initials: NR
authors.lastname: Das
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, Institute for Enzyme Research (KOSOKEN), Tokushima University, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Hara
authors.affiliation: Division of Molecular Neurobiology, Institute for Enzyme Research (KOSOKEN), Tokushima University, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Uchiyama
authors.affiliation: Division of Molecular Neurobiology, Institute for Enzyme Research (KOSOKEN), Tokushima University, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Chida
authors.affiliation: Division of Molecular Neurobiology, Institute for Enzyme Research (KOSOKEN), Tokushima University, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Yano
authors.affiliation: Laboratory of Integrative Biological Science, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, 606-8507, Japan.
authors.forename: Hitomi
authors.initials: H
authors.lastname: Watanabe
authors.affiliation: Laboratory of Integrative Biological Science, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, 606-8507, Japan.
authors.forename: Gen
authors.initials: G
authors.lastname: Kondoh
authors.affiliation: Division of Molecular Neurobiology, Institute for Enzyme Research (KOSOKEN), Tokushima University, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan. sakaguchi@tokushima-u.ac.jp.
authors.forename: Suehiro
authors.initials: S
authors.lastname: Sakaguchi
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D004198:Disease Susceptibility; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017096:Prion Diseases; D000072002:Prion Proteins / Q000235:genetics / Q000378:metabolism*; D020449:Repetitive Sequences, Amino Acid; D017384:Sequence Deletion
chemical_list: D000072002:Prion Proteins