Limited understanding of the functional diversity of N-linked glycans as a major gap of prion biology.

Among a broad range of hypotheses on the molecular nature of transmissible spongiform encephalopathy or scrapie agents discussed in 1960s was a hypothesis of self-replicating polysaccharides. While the studies of the past 40 years provided unambiguous proof that this is not the case, emerging evidence suggests that carbohydrates in the form of sialylated N-linked glycans, which are a constitutive part of mammalian prions or PrP, are essential in determining prion fate in an organism. The current extra-view article discusses recent advancements on the role of N-linked glycans and specifically their sialylation status in controlling prion fate. In addition, this manuscript introduces a new concept on the important role of strain-specific functional carbohydrate epitopes on the PrP surface as main determinants of strain-specific biologic features. According to this concept, individual strain-specific folding patterns of PrP govern selection of PrP sialoglycoforms expressed by a host that can be accommodated within particular PrP structures. Strain-specific patterns of functional carbohydrate epitopes formed by N-linked glycans on PrP surfaces define strain-specific biologic features. As a constitutive part of PrP, the individual strain-specific patterns of carbohydrate epitopes propagate faithfully within a given host as long as individual strain-specific PrP structures are maintained, ensuring inheritance of strain-specific biologic features.