title: Identification of distinct N-terminal truncated forms of prion protein in different Creutzfeldt-Jakob disease subtypes.
abstract: In prion diseases, the cellular prion protein (PrP(C)) is converted to an insoluble and protease-resistant abnormal isoform termed PrP(Sc). In different prion strains, PrP(Sc) shows distinct sites of endogenous or exogenous proteolysis generating a core fragment named PrP27-30. Sporadic Creutzfeldt-Jakob disease (sCJD), the most frequent human prion disease, clinically presents with a variety of neurological signs. As yet, the clinical variability observed in sCJD has not been fully explained by molecular studies relating two major types of PrP27-30 with unglycosylated peptides of 21 (type 1) and 19 kDa (type 2) and the amino acid methionine or valine at position 129. Recently, smaller C-terminal fragments migrating at 12 and 13 kDa have been detected in different sCJD phenotypes, but their significance remains unclear. By using two-dimensional immunoblot with anti-PrP antibodies, we identified two novel groups of protease-resistant PrP fragments in sCJD brain tissues. All sCJD cases with type 1 PrP27-30, in addition to MM subjects with type 2 PrP27-30, were characterized by the presence of unglycosylated PrP fragments of 16-17 kDa. Conversely, brain homogenates from patients VV and MV with type 2 PrP27-30 contained fully glycosylated PrP fragments, which after deglycosylation migrated at 17.5-18 kDa. Interestingly, PrP species of 17.5-18 kDa matched deglycosylated forms of the C1 PrP(C) fragment and were associated with tissue PrP deposition as plaque-like aggregates or amyloid plaques. These data show the presence of multiple PrP(Sc) conformations in sCJD and, in addition, shed new light on the correlation between sCJD phenotypes and disease-associated PrP molecules.
authors.affiliation: Department of Neurological and Visual Sciences, Section of Neurology and Agricultural and Industrial Biotechnologies, University of Verona, 37134 Verona, Italy.
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Zanusso
authors.forename: Alessia
authors.initials: A
authors.lastname: Farinazzo
authors.forename: Frances
authors.initials: F
authors.lastname: Prelli
authors.forename: Michele
authors.initials: M
authors.lastname: Fiorini
authors.forename: Matteo
authors.initials: M
authors.lastname: Gelati
authors.forename: Sergio
authors.initials: S
authors.lastname: Ferrari
authors.forename: Pier Giorgio
authors.initials: PG
authors.lastname: Righetti
authors.forename: Nicolò
authors.initials: N
authors.lastname: Rizzuto
authors.forename: Blas
authors.initials: B
authors.lastname: Frangione
authors.forename: Salvatore
authors.initials: S
authors.lastname: Monaco
mesh_terms: D000328:Adult; D000368:Aged; D001665:Binding Sites; D015153:Blotting, Western; D001921:Brain / Q000196:embryology / Q000378:metabolism; D007562:Creutzfeldt-Jakob Syndrome / Q000378:metabolism*; D003902:Detergents / Q000494:pharmacology; D015180:Electrophoresis, Gel, Two-Dimensional; D005260:Female; D006031:Glycosylation; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D007525:Isoelectric Focusing; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010455:Peptides / Q000737:chemistry; D010641:Phenotype; D018620:PrPSc Proteins / Q000737:chemistry; D011328:Prions / Q000378:metabolism*; D011487:Protein Conformation; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary
chemical_list: D003902:Detergents; D010455:Peptides; D018620:PrPSc Proteins; D011328:Prions; D020033:Protein Isoforms