title: Spontaneous generation of rapidly transmissible prions in transgenic mice expressing wild-type bank vole prion protein.
abstract: Currently, there are no animal models of the most common human prion disorder, sporadic Creutzfeldt-Jakob disease (CJD), in which prions are formed spontaneously from wild-type (WT) prion protein (PrP). Interestingly, bank voles (BV) exhibit an unprecedented promiscuity for diverse prion isolates, arguing that bank vole PrP (BVPrP) may be inherently prone to adopting misfolded conformations. Therefore, we constructed transgenic (Tg) mice expressing WT BVPrP. Tg(BVPrP) mice developed spontaneous CNS dysfunction between 108 and 340 d of age and recapitulated the hallmarks of prion disease, including spongiform degeneration, pronounced astrogliosis, and deposition of alternatively folded PrP in the brain. Brain homogenates of ill Tg(BVPrP) mice transmitted disease to Tg(BVPrP) mice in ∼35 d, to Tg mice overexpressing mouse PrP in under 100 d, and to WT mice in ∼185 d. Our studies demonstrate experimentally that WT PrP can spontaneously form infectious prions in vivo. Thus, Tg(BVPrP) mice may be useful for studying the spontaneous formation of prions, and thus may provide insight into the etiology of sporadic CJD.
authors.affiliation: Institute for Neurodegenerative Diseases, University of California, San Francisco, CA 94143, USA.
authors.forename: Joel C
authors.initials: JC
authors.lastname: Watts
authors.forename: Kurt
authors.initials: K
authors.lastname: Giles
authors.forename: Jan
authors.initials: J
authors.lastname: Stöhr
authors.forename: Abby
authors.initials: A
authors.lastname: Oehler
authors.forename: Sumita
authors.initials: S
authors.lastname: Bhardwaj
authors.forename: Sunny K
authors.initials: SK
authors.lastname: Grillo
authors.forename: Smita
authors.initials: S
authors.lastname: Patel
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: DeArmond
authors.forename: Stanley B
authors.initials: SB
authors.lastname: Prusiner
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D003411:Arvicolinae / Q000235:genetics*; D001921:Brain / Q000473:pathology; D001923:Brain Chemistry; D003062:Codon / Q000235:genetics; D004195:Disease Models, Animal; D017930:Genes, Reporter; D005904:Glial Fibrillary Acidic Protein; D058507:Host Specificity; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics; D017096:Prion Diseases / Q000235:genetics* / Q000473:pathology / Q000635:transmission; D011328:Prions / Q000737:chemistry / Q000235:genetics*; D011401:Promoter Regions, Genetic; D017510:Protein Folding; D017433:Protein Structure, Secondary; D011993:Recombinant Fusion Proteins; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013045:Species Specificity; D014020:Tissue Extracts / Q000633:toxicity
chemical_list: D003062:Codon; D005904:Glial Fibrillary Acidic Protein; D009419:Nerve Tissue Proteins; D011328:Prions; D011993:Recombinant Fusion Proteins; D014020:Tissue Extracts; C528900:glial fibrillary astrocytic protein, mouse