Identification of Distinct N-terminal Truncated Forms of Prion Protein in Different Creutzfeldt-Jakob Disease Subtypes

• Published in: The Journal of biological chemistry Vol. 279; no. 37; pp. 38936 - 38942
• Main Authors: Zanusso, Gianluigi, Farinazzo, Alessia, Prelli, Frances, Fiorini, Michele, Gelati, Matteo, Ferrari, Sergio, Righetti, Pier Giorgio, Rizzuto, Nicolò, Frangione, Blas, Monaco, Salvatore
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.09.2004; American Society for Biochemistry and Molecular Biology
• Subjects: Adult; Aged; Binding Sites; Blotting, Western; Brain - embryology; Brain - metabolism; Creutzfeldt-Jakob Syndrome - metabolism; Detergents - pharmacology; Electrophoresis, Gel, Two-Dimensional; Female; Glycosylation; Humans; Immunoblotting; Immunohistochemistry; Isoelectric Focusing; Male; Middle Aged; Mutation; Peptides - chemistry; Phenotype; Prions - metabolism; Protein Conformation; Protein Isoforms; Protein Structure, Tertiary; PrPSc Proteins - chemistry
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M405468200

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.