Characterization of truncated forms of abnormal prion protein in Creutzfeldt-Jakob disease

Silvio Notari, Rosaria Strammiello, Sabina Capellari, Armin Giese, Maura Cescatti, Jacques Grassi, Bernardino Ghetti, Jan P M Langeveld, Wen Quan Zou, Pierluigi Gambetti, Hans A. Kretzschmar, Piero Parchi

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Abstract

In prion disease, the abnormal conformer of the cellular prion protein, PrPSc, deposits in fibrillar protein aggregates in brain and other organs. Limited exposure of PrPSc to proteolytic digestion in vitro generates a core fragment of 19-21 kDa, named PrP27-30, which is also found in vivo. Recent evidence indicates that abnormal truncated fragments other than PrP27-30 may form in prion disease either in vivo or in vitro. We characterized a novel protease-resistant PrP fragment migrating 2-3 kDa faster than PrP27-30 in Creutzfeldt-Jakob disease (CJD) brains. The fragment has a size of about 18.5 kDa when associated with PrP27-30 type 1 (21 kDa) and of 17 kDa when associated with type 2 (19 kDa). Molecular mass and epitope mapping showed that the two fragments share the primary N-terminal sequence with PrP27-30 types 1 and 2, respectively, but lack a few amino acids at the very end of C terminus together with the glycosylphosphatidylinositol anchor. The amounts of the 18.5- or 17-kDa fragments and the previously described 13-kDa PrPSc C-terminal fragment relatively to the PrP27-30 signal significantly differed among CJD subtypes. Furthermore, protease digestion of PrPSc or PrP27-30 in partially denaturing conditions generated an additional truncated fragment of about 16 kDa only in typical sporadic CJD (i.e. MM1). These results show that the physicochemical heterogeneity of PrPSc in CJD extends to abnormal truncated forms of the protein. The findings support the notion of distinct structural "conformers" of PrPSc and indicate that the characterization of truncated PrPSc forms may further improve molecular typing in CJD.

Original languageEnglish
Pages (from-to)30557-30565
Number of pages9
JournalJournal of Biological Chemistry
Volume283
Issue number45
DOIs
StatePublished - Nov 7 2008

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Creutzfeldt-Jakob Syndrome
Prion Diseases
Digestion
Peptide Hydrolases
Epitope Mapping
Prions
Molecular Typing
Glycosylphosphatidylinositols
Brain
PrPSc Proteins
Amino Acids
Molecular mass
Prion Proteins
Epitopes
Deposits
Proteins
In Vitro Techniques

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Notari, S., Strammiello, R., Capellari, S., Giese, A., Cescatti, M., Grassi, J., ... Parchi, P. (2008). Characterization of truncated forms of abnormal prion protein in Creutzfeldt-Jakob disease. Journal of Biological Chemistry, 283(45), 30557-30565. https://doi.org/10.1074/jbc.M801877200

Characterization of truncated forms of abnormal prion protein in Creutzfeldt-Jakob disease. / Notari, Silvio; Strammiello, Rosaria; Capellari, Sabina; Giese, Armin; Cescatti, Maura; Grassi, Jacques; Ghetti, Bernardino; Langeveld, Jan P M; Zou, Wen Quan; Gambetti, Pierluigi; Kretzschmar, Hans A.; Parchi, Piero.

In: Journal of Biological Chemistry, Vol. 283, No. 45, 07.11.2008, p. 30557-30565.

Research output: Contribution to journalArticle

Notari, S, Strammiello, R, Capellari, S, Giese, A, Cescatti, M, Grassi, J, Ghetti, B, Langeveld, JPM, Zou, WQ, Gambetti, P, Kretzschmar, HA & Parchi, P 2008, 'Characterization of truncated forms of abnormal prion protein in Creutzfeldt-Jakob disease', Journal of Biological Chemistry, vol. 283, no. 45, pp. 30557-30565. https://doi.org/10.1074/jbc.M801877200
Notari S, Strammiello R, Capellari S, Giese A, Cescatti M, Grassi J et al. Characterization of truncated forms of abnormal prion protein in Creutzfeldt-Jakob disease. Journal of Biological Chemistry. 2008 Nov 7;283(45):30557-30565. https://doi.org/10.1074/jbc.M801877200
Notari, Silvio ; Strammiello, Rosaria ; Capellari, Sabina ; Giese, Armin ; Cescatti, Maura ; Grassi, Jacques ; Ghetti, Bernardino ; Langeveld, Jan P M ; Zou, Wen Quan ; Gambetti, Pierluigi ; Kretzschmar, Hans A. ; Parchi, Piero. / Characterization of truncated forms of abnormal prion protein in Creutzfeldt-Jakob disease. In: Journal of Biological Chemistry. 2008 ; Vol. 283, No. 45. pp. 30557-30565.
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AU - Grassi, Jacques

AU - Ghetti, Bernardino

AU - Langeveld, Jan P M

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