title: Guinea Pig Prion Protein Supports Rapid Propagation of Bovine Spongiform Encephalopathy and Variant Creutzfeldt-Jakob Disease Prions.
abstract: The biochemical and neuropathological properties of bovine spongiform encephalopathy (BSE) and variant Creutzfeldt-Jakob disease (vCJD) prions are faithfully maintained upon transmission to guinea pigs. However, primary and secondary transmissions of BSE and vCJD in guinea pigs result in long incubation periods of ∼450 and ∼350 days, respectively. To determine if the incubation periods of BSE and vCJD prions could be shortened, we generated transgenic (Tg) mice expressing guinea pig prion protein (GPPrP). Inoculation of Tg(GPPrP) mice with BSE and vCJD prions resulted in mean incubation periods of 210 and 199 days, respectively, which shortened to 137 and 122 days upon serial transmission. In contrast, three different isolates of sporadic CJD prions failed to transmit disease to Tg(GPPrP) mice. Many of the strain-specified biochemical and neuropathological properties of BSE and vCJD prions, including the presence of type 2 protease-resistant PrPSc, were preserved upon propagation in Tg(GPPrP) mice. Structural modeling revealed that two residues near the N-terminal region of α-helix 1 in GPPrP might mediate its susceptibility to BSE and vCJD prions. Our results demonstrate that expression of GPPrP in Tg mice supports the rapid propagation of BSE and vCJD prions and suggest that Tg(GPPrP) mice may serve as a useful paradigm for bioassaying these prion isolates.
  
  
  
  Variant Creutzfeldt-Jakob disease (vCJD) and bovine spongiform encephalopathy (BSE) prions are two of the prion strains most relevant to human health. However, propagating these strains in mice expressing human or bovine prion protein has been difficult because of prolonged incubation periods or inefficient transmission. Here, we show that transgenic mice expressing guinea pig prion protein are fully susceptible to vCJD and BSE prions but not to sporadic CJD prions. Our results suggest that the guinea pig prion protein is a better, more rapid substrate than either bovine or human prion protein for propagating BSE and vCJD prions.
authors.affiliation: Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, California, USA Department of Neurology, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Joel C
authors.initials: JC
authors.lastname: Watts
authors.affiliation: Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, California, USA Department of Neurology, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Kurt
authors.initials: K
authors.lastname: Giles
authors.affiliation: California Institute for Quantitative Biosciences (QB3), University of California, San Francisco, San Francisco, California, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Saltzberg
authors.affiliation: Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, California, USA Department of Neurology, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Brittany N
authors.initials: BN
authors.lastname: Dugger
authors.affiliation: Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Smita
authors.initials: S
authors.lastname: Patel
authors.affiliation: Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Abby
authors.initials: A
authors.lastname: Oehler
authors.affiliation: Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Sumita
authors.initials: S
authors.lastname: Bhardwaj
authors.affiliation: California Institute for Quantitative Biosciences (QB3), University of California, San Francisco, San Francisco, California, USA Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, USA Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Andrej
authors.initials: A
authors.lastname: Sali
authors.affiliation: Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, California, USA Department of Neurology, University of California, San Francisco, San Francisco, California, USA Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, California, USA stanley.prusiner@ucsf.edu.
authors.forename: Stanley B
authors.initials: SB
authors.lastname: Prusiner
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D002417:Cattle; D007562:Creutzfeldt-Jakob Syndrome / Q000378:metabolism / Q000473:pathology* / Q000635:transmission; D016643:Encephalopathy, Bovine Spongiform / Q000378:metabolism / Q000473:pathology* / Q000635:transmission; D006168:Guinea Pigs; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D000072002:Prion Proteins / Q000378:metabolism*; D011328:Prions / Q000378:metabolism*
chemical_list: D000072002:Prion Proteins; D011328:Prions