Glycosylation differences between the normal and pathogenic prion protein isoforms

Prion protein consists of an ensemble of glycosylated variants or glycoform s. The enzymes that direct oligosaccharide processing, and hence control th e glycan profile for any given glycoprotein, are often exquisitely sensitiv e to other events taking place within the cell in which the glycoprotein is expressed. Alterations in the populations of sugars attached to proteins c an reflect changes caused, for example, by developmental processes or by di sease. Here we report that normal (PrPC) and pathogenic (PrPSc) prion prote ins (PrP) from Syrian hamsters contain the same set of at least 52 bi-, tri -, and tetraantennary N-linked oligosaccharides, although the relative prop ortions of individual glycans differ. This conservation of structure sugges ts that the conversion of PrPC into PrPSc is not confined to a subset of Pr Ps that contain specific sugars. Compared with PrPC, PrPSc contains decreas ed levels of glycans with bisecting GlcNAc residues and increased levels of tri- and tetraantennary sugars. This change is consistent with a decrease in the activity of N-acetylglucosaminyltransferase III (GnTIII) toward PrPC in cells where PrPSc is formed and argues that, in at least some cells for ming PrPSc, the glycosylation machinery has been perturbed. The reduction i n GnTIII activity is intriguing both with respect to the pathogenesis of th e prion disease and the replication pathway for prions.