title: Two-dimensional mapping of three phenotype-associated isoforms of the prion protein in sporadic Creutzfeldt-Jakob disease.
abstract: Transmissible spongiform encephalopathies (TSE), or prion diseases, are mammalian neurodegenerative disorders characterized by a conformational modification of the host-encoded prion protein (PrP(C)) into an isoform which is detergent-insoluble and partially resistant to protease treatment (PrP(Sc)). Distinct types of PrP(Sc), differing in conformation and variation in the relative amount of their glycoforms, have been associated with different phenotypes of TSE. In sporadic Creutzfeldt-Jakob disease (sCJD), two major types of PrP(Sc), with proteinase K (PK)-resistant fragments of 21 and 19 kDa, have been described. No consensus exists, however, on the molecular classification of PrP(Sc) in sCJD, since further heterogeneity within PrPSc conformers has been reported. We studied 19 subjects with dementia or dementia/ataxia at onset and 12 subjects with ataxia at onset. Following two-dimensional gel electrophoresis, we characterized PrP(C) and PrP(Sc) species in normal and sCJD brains by immunoblotting with antibodies recognizing N-terminal and C-terminal PrP regions. Three types of PrP(Sc) were detected in detergent-insoluble fractions from sCJD brains, mainly consisting of full-length PrP(Sc) in subjects with rapidly progressive dementia, and two different sets of amino-truncated PrP(Sc) glycoforms in subjects with dementia/ataxia and ataxia at onset. Examination of the PrP(Sc) core fragment, following PK treatment and deglycosylation, confirmed the existence of three distinctive patterns. These findings have immediate implications for the molecular classification of sCJD.
authors.affiliation: Section of Clinical Neurology, Department of Neurological and Visual Sciences, University of Verona, Verona, Italy.
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Zanusso
authors.forename: Pier Giorgio
authors.initials: PG
authors.lastname: Righetti
authors.forename: Sergio
authors.initials: S
authors.lastname: Ferrari
authors.forename: Liliana
authors.initials: L
authors.lastname: Terrin
authors.forename: Alessia
authors.initials: A
authors.lastname: Farinazzo
authors.forename: Franco
authors.initials: F
authors.lastname: Cardone
authors.forename: Maurizio
authors.initials: M
authors.lastname: Pocchiari
authors.forename: Nicola
authors.initials: N
authors.lastname: Rizzuto
authors.forename: Salvatore
authors.initials: S
authors.lastname: Monaco
mesh_terms: D001923:Brain Chemistry; D002525:Cerebellar Cortex / Q000737:chemistry; D007562:Creutzfeldt-Jakob Syndrome; D003704:Dementia; D015180:Electrophoresis, Gel, Two-Dimensional / Q000379:methods; D006023:Glycoproteins / Q000032:analysis; D006801:Humans; D010449:Peptide Mapping / Q000379:methods; D010641:Phenotype; D018621:PrPC Proteins / Q000032:analysis*; D018620:PrPSc Proteins / Q000032:analysis*; D020033:Protein Isoforms / Q000032:analysis; D017384:Sequence Deletion
chemical_list: D006023:Glycoproteins; D018621:PrPC Proteins; D018620:PrPSc Proteins; D020033:Protein Isoforms