title: Mutant PrPCJD prevails over wild-type PrPCJD in the brain of V210I and R208H genetic Creutzfeldt-Jakob disease patients.
abstract: Creutzfeldt-Jakob disease (CJD) is a neurodegenerative disorder characterized by the deposition of the pathological conformer (PrP(CJD)) of the host encoded cellular prion protein (PrP(C)). In genetic CJD associated with V210I or R208H PrP substitutions, the pathogenic role of mutant residues is still poorly understood. To understand how V210I or R208H PrP mutations facilitate the development of the disease, we determined by mass spectrometry the quantitative ratio of mutant/wild-type PrP(CJD) allotypes in brains from affected subjects. We found that the mutant PrP(CJD) allotypes moderately exceeds of 2- or 3-fold the amount of the wild-type counterpart suggesting that these mutations mainly exert their pathogenic effect on the onset of the pathogenic cascade. Different mechanisms can be hypothesized to explain the pathogenic role of mutant residues: V210I and R208H substitutions can increase the concentration of PrP(C) and the probability to form insoluble aggregates, or they may facilitate the formation of pathological intermediates, or, alternatively, they may increase the affinity for ligands that are involved in the initial phases of PrP(CJD) formation and aggregation. Whatever the mechanism, the enrichment found for the mutated PrP(CJD) species indicates that these altered structures are more prone, with respect to the non-mutated ones, to be captured in the polymerization process either at the onset or during the development of the disease.
authors.affiliation: Dipartimento di Biologia Cellulare e Neuroscienze, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy. Electronic address: franco.cardone@iss.it.
authors.forename: Franco
authors.initials: F
authors.lastname: Cardone
authors.affiliation: Dipartimento di Biologia Cellulare e Neuroscienze, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Principe
authors.affiliation: Dipartimento di Scienze Biochimiche, "Sapienza" University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy.
authors.forename: Maria Eugenia
authors.initials: ME
authors.lastname: Schininà
authors.affiliation: Dipartimento di Scienze Biochimiche, "Sapienza" University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy.
authors.forename: Bruno
authors.initials: B
authors.lastname: Maras
authors.affiliation: Dipartimento di Scienze Biomediche e Neuromotorie, University of Bologna, Via Ugo Foscolo 7, 40123 Bologna, Italy; IRCCS, Istituto delle Scienze Neurologiche, Via Altura 3, 40139 Bologna, Italy.
authors.forename: Sabina
authors.initials: S
authors.lastname: Capellari
authors.affiliation: Dipartimento di Scienze Biomediche e Neuromotorie, University of Bologna, Via Ugo Foscolo 7, 40123 Bologna, Italy; IRCCS, Istituto delle Scienze Neurologiche, Via Altura 3, 40139 Bologna, Italy.
authors.forename: Piero
authors.initials: P
authors.lastname: Parchi
authors.affiliation: Dipartimento di Scienze Biomediche e Neuromotorie, University of Bologna, Via Ugo Foscolo 7, 40123 Bologna, Italy.
authors.forename: Silvio
authors.initials: S
authors.lastname: Notari
authors.affiliation: Dipartimento di Scienze Biochimiche, "Sapienza" University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Di Francesco
authors.affiliation: Dipartimento di Biologia Cellulare e Neuroscienze, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Poleggi
authors.affiliation: Dipartimento di Biologia Cellulare e Neuroscienze, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Galeno
authors.affiliation: Dipartimento di Biologia Cellulare e Neuroscienze, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.
authors.forename: Ramona
authors.initials: R
authors.lastname: Vinci
authors.affiliation: Dipartimento di Biologia Cellulare e Neuroscienze, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Mellina
authors.affiliation: Dipartimento di Biologia Cellulare e Neuroscienze, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.
authors.forename: Susanna
authors.initials: S
authors.lastname: Almonti
authors.affiliation: Dipartimento di Biologia Cellulare e Neuroscienze, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Ladogana
authors.affiliation: Dipartimento di Biologia Cellulare e Neuroscienze, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Pocchiari
mesh_terms: D001921:Brain / Q000378:metabolism / Q000473:pathology*; D007562:Creutzfeldt-Jakob Syndrome / Q000235:genetics* / Q000473:pathology; D005838:Genotype; D006801:Humans; D013058:Mass Spectrometry; D017354:Point Mutation; D018620:PrPSc Proteins / Q000032:analysis / Q000235:genetics*; D017510:Protein Folding
chemical_list: D018620:PrPSc Proteins
keywords: Amyloidogenesis; PrP allotypes; PrP(27–30); Quantitative MS; TSE; gCJD