Prion protein glycosylation is sensitive to redox change

The conversion of soluble prion protein into an insoluble, pathogenic, prot ease-resistant isoform is a key event in the development of prion diseases. Although the mechanism by which the conversion engenders a pathogenic even t is unclear, there is increasing evidence to suggest that this may depend on the function of the prion protein in preventing oxidative damage. Theref ore, in this study, we assessed the interrelationship between redox-sensiti ve cysteine, glycosylation, and prion metabolism. Cells were treated with a thioreductant, dithiothreitol, to assess the effect of the cellular oxidat ion state on the synthesis of the prion protein. This change in redox balan ce affected the glycosylation of the prion protein, resulting in the sole p roduction of glycosylated forms. The role of the single disulfide bridge in mediating this effect within the prion protein was confirmed by mutating t he cysteine residues involved in its formation. These data suggest that con ditions that increase the rate of formation of the disulfide bridge favor f ormation of the unglycosylated prion protein. Thus, since the presence of g lycans on the prion protein is protective against its pathogenic conversion , a change in the redox status of the cell would increase the risk of devel oping a prion disease by favoring the production of the unglycosylated form .