title: Abbreviated incubation times for human prions in mice expressing a chimeric mouse-human prion protein transgene.
abstract: Transgenic (Tg) mouse lines that express chimeric mouse-human prion protein (PrP), designated MHu2M, are susceptible to prions from patients with sporadic Creutzfeldt-Jakob disease (sCJD). With the aim of decreasing the incubation time to fewer than 200 days, we constructed transgenes in which one or more of the nine human residues in MHu2M were changed to mouse. The construct with murine residues at positions 165 and 167 was expressed in Tg(MHu2M,M165V,E167Q) mice and resulted in shortening the incubation time to approximately 110 days for prions from sCJD patients. The construct with a murine residue at position 96 resulted in lengthening the incubation time to more than 280 days for sCJD prions. When murine residues 96, 165, and 167 were expressed, the abbreviated incubation times for sCJD prions were abolished. Variant CJD prions showed prolonged incubation times between 300 and 700 days in Tg(MHu2M) mice on first passage and incubation times of approximately 350 days in Tg(MHu2M,M165V,E167Q) mice. On second and third passages of variant CJD prions in Tg(MHu2M) mice, multiple strains of prions were detected based on incubation times and the sizes of the protease-resistant, deglycosylated PrP(Sc) fragments. Our discovery of a previously undescribed chimeric transgene with abbreviated incubation times for sCJD prions should facilitate studies on the prion species barrier and human prion diversity.
authors.affiliation: Institute for Neurodegenerative Diseases and Department of Neurology, University of California, San Francisco, CA 94143, USA.
authors.forename: Carsten
authors.initials: C
authors.lastname: Korth
authors.forename: Kiyotoshi
authors.initials: K
authors.lastname: Kaneko
authors.forename: Darlene
authors.initials: D
authors.lastname: Groth
authors.forename: Norbert
authors.initials: N
authors.lastname: Heye
authors.forename: Glenn
authors.initials: G
authors.lastname: Telling
authors.forename: James
authors.initials: J
authors.lastname: Mastrianni
authors.forename: Piero
authors.initials: P
authors.lastname: Parchi
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Gambetti
authors.forename: Robert
authors.initials: R
authors.lastname: Will
authors.forename: James
authors.initials: J
authors.lastname: Ironside
authors.forename: Cornelia
authors.initials: C
authors.lastname: Heinrich
authors.forename: Patrick
authors.initials: P
authors.lastname: Tremblay
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: DeArmond
authors.forename: Stanley B
authors.initials: SB
authors.lastname: Prusiner
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D007562:Creutzfeldt-Jakob Syndrome / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D016297:Mutagenesis, Site-Directed; D018620:PrPSc Proteins / Q000235:genetics / Q000378:metabolism; D017096:Prion Diseases / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011328:Prions / Q000235:genetics* / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D013045:Species Specificity; D013997:Time Factors
chemical_list: D018620:PrPSc Proteins; D011328:Prions; D011993:Recombinant Fusion Proteins