NR ARBG
AU Zanusso,G.; Farinazzo,A.; Prelli,F.; Fiorini,M.; Gelati,M.; Ferrari,S.; Righetti,P.G.; Rizzuto,N.; Frangione,B.; Monaco,S.
TI Identification of distinct N-terminal truncated forms of prion protein in different Creutzfeldt-Jakob disease subtypes
QU The Journal of Biological Chemistry 2004 Sep 10; 279(37): 38936-42
PT journal article
AB In prion diseases, the cellular prion protein (PrPc) is converted to an insoluble and protease-resistant abnormal isoform termed PrPsc. In different prion strains, PrPsc 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 PrPc fragment and were associated with tissue PrP deposition as plaque-like aggregates or amyloid plaques. These data show the presence of multiple PrPsc conformations in sCJD and, in addition, shed new light on the correlation between sCJD phenotypes and disease-associated PrP molecules.
MH Adult; Aged; Binding Sites; Blotting, Western; Brain/embryology/metabolism; Creutzfeldt-Jakob Syndrome/*metabolism; Detergents/pharmacology; Electrophoresis, Gel, Two-Dimensional; Female; Glycosylation; Human; Immunoblotting; Immunohistochemistry; Isoelectric Focusing; Male; Middle Aged; Mutation; Peptides/chemistry; Phenotype; PrPsc Proteins/chemistry; Prions/*metabolism; Protein Conformation; Protein Isoforms; Protein Structure, Tertiary; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S.
AD Department of Neurological and Visual Sciences, Section of Neurology and Agricultural and Industrial Biotechnologies, University of Verona, 37134 Verona, Italy.
SP englisch
PO USA