title: Absence of spontaneous disease and comparative prion susceptibility of transgenic mice expressing mutant human prion proteins.
abstract: Approximately 15 % of human prion disease is associated with autosomal-dominant pathogenic mutations in the prion protein (PrP) gene. Previous attempts to model these diseases in mice have expressed human PrP mutations in murine PrP, but this may have different structural consequences. Here, we describe transgenic mice expressing human PrP with P102L or E200K mutations and methionine (M) at the polymorphic residue 129. Although no spontaneous disease developed in aged animals, these mice were readily susceptible to prion infection from patients with the homotypic pathogenic mutation. However, while variant Creutzfeldt-Jakob disease (CJD) prions transmitted infection efficiently to both lines of mice, markedly different susceptibilities to classical (sporadic and iatrogenic) CJD prions were observed. Prions from E200K and classical CJD M129 homozygous patients, transmitted disease with equivalent efficiencies and short incubation periods in human PrP 200K, 129M transgenic mice. However, mismatch at residue 129 between inoculum and host dramatically increased the incubation period. In human PrP 102L, 129M transgenic mice, short disease incubation periods were only observed with transmissions of prions from P102L patients, whereas classical CJD prions showed prolonged and variable incubation periods irrespective of the codon 129 genotype. Analysis of disease-related PrP (PrP(Sc)) showed marked alteration in the PrP(Sc) glycoform ratio propagated after transmission of classical CJD prions, consistent with the PrP point mutations directly influencing PrP(Sc) assembly. These data indicate that P102L or E200K mutations of human PrP have differing effects on prion propagation that depend upon prion strain type and can be significantly influenced by mismatch at the polymorphic residue 129.
authors.affiliation: MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK.
authors.forename: Emmanuel A
authors.initials: EA
authors.lastname: Asante
authors.affiliation: MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK.
authors.forename: Ian
authors.initials: I
authors.lastname: Gowland
authors.affiliation: MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Grimshaw
authors.affiliation: MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK.
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Linehan
authors.affiliation: MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK.
authors.forename: Michelle
authors.initials: M
authors.lastname: Smidak
authors.affiliation: MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Houghton
authors.affiliation: MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK.
authors.forename: Olufunmilayo
authors.initials: O
authors.lastname: Osiguwa
authors.affiliation: MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Tomlinson
authors.affiliation: MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK.
authors.forename: Susan
authors.initials: S
authors.lastname: Joiner
authors.affiliation: MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Brandner
authors.affiliation: MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK.
authors.forename: Jonathan D F
authors.initials: JDF
authors.lastname: Wadsworth
authors.affiliation: MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK.
authors.forename: John
authors.initials: J
authors.lastname: Collinge
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D007562:Creutzfeldt-Jakob Syndrome / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000635:transmission*; D004198:Disease Susceptibility; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D017354:Point Mutation; D017096:Prion Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000635:transmission*; D011328:Prions / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity*; D019076:Transgenes
chemical_list: D011328:Prions