title: Prion Strain Characterization of a Novel Subtype of Creutzfeldt-Jakob Disease.
abstract: In 2007, we reported a patient with an atypical form of Creutzfeldt-Jakob disease (CJD) heterozygous for methionine-valine (MV) at codon 129 who showed a novel pathological prion protein (PrPTSE) conformation with an atypical glycoform (AG) profile and intraneuronal PrP deposition. In the present study, we further characterize the conformational properties of this pathological prion protein (PrPTSEMVAG), showing that PrPTSEMVAGis composed of multiple conformers with biochemical properties distinct from those of PrPTSEtype 1 and type 2 of MV sporadic CJD (sCJD). Experimental transmission of CJD-MVAGto bank voles and gene-targeted transgenic mice carrying the human prion protein gene (TgHu mice) showed unique transmission rates, survival times, neuropathological changes, PrPTSEdeposition patterns, and PrPTSEglycotypes that are distinct from those of sCJD-MV1 and sCJD-MV2. These biochemical and experimental data suggest the presence of a novel prion strain in CJD-MVAGIMPORTANCESporadic Creutzfeldt-Jakob disease is caused by the misfolding of the cellular prion protein, which assumes two different major conformations (type 1 and type 2) and, together with the methionine/valine polymorphic codon 129 of the prion protein gene, contribute to the occurrence of distinct clinical-pathological phenotypes. Inoculation in laboratory rodents of brain tissues from the six possible combinations of pathological prion protein types with codon 129 genotypes results in the identification of 3 or 4 strains of prions. We report on the identification of a novel strain of Creutzfeldt-Jakob disease isolated from a patient who carried an abnormally glycosylated pathological prion protein. This novel strain has unique biochemical characteristics, does not transmit to humanized transgenic mice, and shows exclusive transmission properties in bank voles. The identification of a novel human prion strain improves our understanding of the pathogenesis of the disease and of possible mechanisms of prion transmission.
authors.affiliation: Department of Neurosciences, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Galeno
authors.affiliation: Department of Food Safety and Veterinary Public Health, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Michele Angelo
authors.initials: MA
authors.lastname: Di Bari
authors.affiliation: Department of Food Safety and Veterinary Public Health, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Romolo
authors.initials: R
authors.lastname: Nonno
authors.affiliation: Department of Neurosciences, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Cardone
authors.affiliation: Department of Neurosciences, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Sbriccoli
authors.affiliation: Department of Neurosciences, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Graziano
authors.affiliation: Department of Neurosciences, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Loredana
authors.initials: L
authors.lastname: Ingrosso
authors.affiliation: Department of Neurosciences, Biomedicine and Movement Sciences, Section of Neurology, University of Verona, Verona, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Fiorini
authors.affiliation: Department of Neurosciences, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Angelina
authors.initials: A
authors.lastname: Valanzano
authors.affiliation: Department of Neurosciences, Biomedicine and Movement Sciences, Section of Neurology, University of Verona, Verona, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Pasini
authors.affiliation: Department of Neurosciences, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Poleggi
authors.affiliation: Department of Neurosciences, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Ramona
authors.initials: R
authors.lastname: Vinci
authors.affiliation: Department of Neurosciences, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Ladogana
authors.affiliation: Department of Neurosciences, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Puopolo
authors.affiliation: Department of Neurosciences, Biomedicine and Movement Sciences, Section of Neurology, University of Verona, Verona, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Monaco
authors.affiliation: Department of Food Safety and Veterinary Public Health, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Umberto
authors.initials: U
authors.lastname: Agrimi
authors.affiliation: Department of Neurosciences, Biomedicine and Movement Sciences, Section of Neurology, University of Verona, Verona, Italy gianluigi.zanusso@univr.it maurizio.pocchiari@iss.it.
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Zanusso
authors.affiliation: Department of Neurosciences, Istituto Superiore di Sanità, Rome, Italy gianluigi.zanusso@univr.it maurizio.pocchiari@iss.it.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Pocchiari
mesh_terms: D000818:Animals; D003411:Arvicolinae; D001921:Brain / Q000473:pathology; D001923:Brain Chemistry; D007562:Creutzfeldt-Jakob Syndrome / Q000378:metabolism / Q000473:pathology / Q000635:transmission*; D005838:Genotype; D006801:Humans; D008715:Methionine; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D000072002:Prion Proteins / Q000737:chemistry* / Q000378:metabolism; D011328:Prions / Q000737:chemistry* / Q000145:classification / Q000378:metabolism; D011487:Protein Conformation; D014633:Valine
chemical_list: D000072002:Prion Proteins; D011328:Prions; D008715:Methionine; D014633:Valine
keywords: Creutzfeldt-Jakob disease; humanized mice; prion strain; prions