Glycosylation of prion strains in transmissible spongiform encephalopathies

This is a review of prion replication in the context of the cell biology of membrane proteins especially folding quality control in the endoplasmic reticulum (ER). Transmissible spongiform encephalopathies, such as scrapie and BSE, are infectious lethal diseases of mammalian neurons characterised by conversion of the normal membrane protein PrPC to the disease-associated conformational isomer called PrPSc. Pr-Sc, apparently responsible for infectivity, forms a number of different conformations and specific N-glycosylation site occupancies that correlate with TSE strain differences. Dimerisation and specific binding of PrPC and PrPSc seems critical in PrPSc biosynthesis and is influenced by N-glycosylation and disulfide bond formation. PrPSc can be amplified in vitro but new glycosylation cannot occur in cell free environments without the special conditions of microsome mediated in vitro translation, thus strain specific glycosylation of PrPSc formed in vitro in the absence of these conditions must take place by imprintation of PrPC from existing glycosylation site-occupancies. PrPSc formed in cell free homogenates is not infectious pointing to events necessary for infectivity that only occur in intact cells. Such events may include glycosylation site occupancy and ER folding chaperone activity. In the biosynthetic pathway of PrPSc, early acquisition of sensitivity of the GPI anchor to phospholipase C can be distinguished from the later acquisition of protease resistance and detergent insolubility. By analogy to the co-translational formation of the MHC I loading complex, it is postulated that PrPSc or its specific peptides could imprint nascent PrPC chains thereby ensuring its own folds and the observed glycosylation site occupancy ratios of strains.