title: Novel strain properties distinguishing sporadic prion diseases sharing prion protein genotype and prion type.
abstract: In most human sporadic prion diseases the phenotype is consistently associated with specific pairings of the genotype at codon 129 of the prion protein gene and conformational properties of the scrapie PrP (PrPSc) grossly identified types 1 and 2. This association suggests that the 129 genotype favours the selection of a distinct strain that in turn determines the phenotype. However, this mechanism cannot play a role in the phenotype determination of sporadic fatal insomnia (sFI) and a subtype of sporadic Creutzfeldt-Jakob disease (sCJD) identified as sCJDMM2, which share 129 MM genotype and PrPSctype 2 but are associated with quite distinct phenotypes. Our detailed comparative study of the PrPScconformers has revealed major differences between the two diseases, which preferentially involve the PrPSccomponent that is sensitive to digestion with proteases (senPrPSc) and to a lesser extent the resistant component (resPrPSc). We conclude that these variations are consistent with two distinct strains in sFI and sCJDMM2, and that the rarer sFI is the result of a variant strain selection pathway that might be favoured by a different brain site of initial PrPScformation in the two diseases.
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Laura
authors.initials: L
authors.lastname: Cracco
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Silvio
authors.initials: S
authors.lastname: Notari
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Ignazio
authors.initials: I
authors.lastname: Cali
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Man-Sun
authors.initials: MS
authors.lastname: Sy
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Shu G
authors.initials: SG
authors.lastname: Chen
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio, United States of America.|National Prion Disease Pathology Surveillance Center, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Cohen
authors.affiliation: Department of Pathology and Laboratory Medicine, Division of Neuropathology, Indiana University, Indianapolis, Indiana, United States of America.
authors.forename: Bernardino
authors.initials: B
authors.lastname: Ghetti
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio, United States of America.|National Prion Disease Pathology Surveillance Center, Case Western Reserve University, Cleveland, Ohio, United States of America.|Department of Neurology, Case Western Reserve University, Cleveland, Ohio, United States of America.|Department of Psychiatry, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Brian S
authors.initials: BS
authors.lastname: Appleby
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio, United States of America.|National Prion Disease Pathology Surveillance Center, Case Western Reserve University, Cleveland, Ohio, United States of America.|Department of Neurology, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Wen-Quan
authors.initials: WQ
authors.lastname: Zou
authors.affiliation: Laboratory of Persistent Viral Diseases, NIH/NIAID Rocky Mountain Laboratories, Hamilton, Montana, United States of America.
authors.forename: Byron
authors.initials: B
authors.lastname: Caughey
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio, United States of America.|National Prion Disease Pathology Surveillance Center, Case Western Reserve University, Cleveland, Ohio, United States of America.|Department of Neurology, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Jiri G
authors.initials: JG
authors.lastname: Safar
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Gambetti
mesh_terms: D007562:Creutzfeldt-Jakob Syndrome / Q000235:genetics / Q000378:metabolism; D005838:Genotype; D006031:Glycosylation; D006801:Humans; D034062:Insomnia, Fatal Familial / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D018620:PrPSc Proteins / Q000235:genetics / Q000378:metabolism; D017096:Prion Diseases / Q000145:classification* / Q000235:genetics; D000072002:Prion Proteins / Q000235:genetics* / Q000378:metabolism; D011328:Prions / Q000145:classification* / Q000235:genetics
chemical_list: D018620:PrPSc Proteins; D000072002:Prion Proteins; D011328:Prions