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

ABSTRACT

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^Sc, 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^Sc surface as main determinants of strain-specific biologic features. According to this concept, individual strain-specific folding patterns of PrP^Sc govern selection of PrP^C sialoglycoforms expressed by a host that can be accommodated within particular PrP^Sc structures. Strain-specific patterns of functional carbohydrate epitopes formed by N-linked glycans on PrP^Sc surfaces define strain-specific biologic features. As a constitutive part of PrP^Sc, the individual strain-specific patterns of carbohydrate epitopes propagate faithfully within a given host as long as individual strain-specific PrP^Sc structures are maintained, ensuring inheritance of strain-specific biologic features.

KEYWORDS:

• carbohydrate epitopes
• microglia
• N-linked glycans
• prion
• prion diseases
• sialylation
• sialic acid
• secondary lymphoid organs

This article refers to:

ABBREVIATIONS

PrPC	=	normal cellular isoform of the prion protein
PrPSc	=	abnormal, disease-associated isoform of the prion protein

DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST

No potential conflicts of interest were disclosed.

ACKNOWLEDGMENT

We thank Pamela Wright for editing the manuscript.

FUNDING

This work was supported by NIH grant NS045585 to IVB.