Characterization of the F198S prion protein mutation: Enhanced glycosylation and defective refolding

• Published in: Journal of Alzheimer's disease Vol. 7; no. 2; pp. 159 - 171
• Main Authors: Zaidi, Syed I.A., Richardson, Sandra L., Capellari, Sabina, Song, Li, Smith, Mark A., Ghetti, Bernardino, Sy, Man-Sun, Gambetti, Pierluigi, Petersen, Robert B.
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 01.04.2005
• Subjects: Amyloid - genetics; Binding Sites; Brain - metabolism; Cell Extracts; DNA Mutational Analysis; DNA Primers - genetics; Endopeptidase K - metabolism; Gerstmann-Straussler-Scheinker Disease - genetics; Gerstmann-Straussler-Scheinker Disease - metabolism; Glycosylation; Humans; Immunoprecipitation; Point Mutation - genetics; Prions - genetics; Protein Conformation; Protein Folding; Protein Precursors - metabolism; PrPSc Proteins - metabolism; Subcellular Fractions - metabolism
• ISSN: 1387-2877; 1875-8908
• DOI: 10.3233/JAD-2005-7209

Prion diseases are associated with the accumulation of a misfolded, protease resistant form of the prion protein, PrPres. In humans there are a variety of different prion related diseases that are sporadic, inherited, or acquired by infection. Gerstmann-Straussler-Sheinker syndrome (GSS) is an inherited prion disease in which PrPres accumulates as amorphous aggregates as well as in amyloid plaques. GSS has been associated with a variety of point mutations in the prion protein: 102, 105, 117, 131, 145, 187, 198, 202, 212, 217, and 232. The F198S mutation was discovered in a large Indiana kindred. Previous studies in vitro have shown that the 198 mutation results in structural instability of the prion protein. In the current study, we demonstrate in a cell model that the F198S mutant protein can be folded properly in a cellular context, but is unable to refold to a native state after denaturation. Further, the F198S mutation significantly affects glycosylation of the mutant protein.