title: Dissociation of pathological and molecular phenotype of variant Creutzfeldt-Jakob disease in transgenic human prion protein 129 heterozygous mice.
abstract: All neuropathologically confirmed cases of variant Creutzfeldt-Jakob disease (vCJD), characterized by abundant florid plaques and type 4 disease-related prion protein (PrP(Sc)) in the brain, have been homozygous for methionine at polymorphic residue 129 of PRNP. The distinctive neuropathological and molecular phenotype of vCJD can be faithfully recapitulated in Prnp-null transgenic mice homozygous for human PrP M129 but not V129, where a distinct prion strain is propagated. Here we model susceptibility of 129MV heterozygotes, the most common PRNP genotype, in transgenic mice and show that, remarkably, propagation of type 4 PrP(Sc) was not associated with characteristic vCJD neuropathology. Depending on the source of the inoculum these mice can develop four distinct disease phenotypes after challenge with bovine spongiform encephalopathy (BSE) prions or vCJD (human-passaged BSE) prions. vCJD-challenged mice had higher attack rates of prion infection than BSE-challenged recipients. These data argue that human PRNP 129 heterozygotes will be more susceptible to infection with vCJD prions than to cattle BSE prions and may present with a neuropathological phenotype distinct from vCJD.
authors.affiliation: Medical Research Council Prion Unit and Department of Neurodegenerative Disease, Institute of Neurology, University College London, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, United Kingdom.
authors.forename: Emmanuel A
authors.initials: EA
authors.lastname: Asante
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Linehan
authors.forename: Ian
authors.initials: I
authors.lastname: Gowland
authors.forename: Susan
authors.initials: S
authors.lastname: Joiner
authors.forename: Katie
authors.initials: K
authors.lastname: Fox
authors.forename: Sharon
authors.initials: S
authors.lastname: Cooper
authors.forename: Olufumilayo
authors.initials: O
authors.lastname: Osiguwa
authors.forename: Michelle
authors.initials: M
authors.lastname: Gorry
authors.forename: Julie
authors.initials: J
authors.lastname: Welch
authors.forename: Richard
authors.initials: R
authors.lastname: Houghton
authors.forename: Melanie
authors.initials: M
authors.lastname: Desbruslais
authors.forename: Sebastian
authors.initials: S
authors.lastname: Brandner
authors.forename: Jonathan D F
authors.initials: JD
authors.lastname: Wadsworth
authors.forename: John
authors.initials: J
authors.lastname: Collinge
mesh_terms: D000818:Animals; D002417:Cattle; D007562:Creutzfeldt-Jakob Syndrome / Q000235:genetics* / Q000473:pathology*; D016643:Encephalopathy, Bovine Spongiform / Q000378:metabolism / Q000473:pathology; D006580:Genetic Carrier Screening; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D011328:Prions / Q000235:genetics*
chemical_list: D011328:Prions