Multifaceted Role of Sialylation in Prion Diseases

Abstract

Mammalian prion or PrP(Sc) is a proteinaceous infectious agent that consists of a misfolded, self-replicating state of a sialoglycoprotein called the prion protein, or PrP(C). Sialylation of the prion protein N-linked glycans was discovered more than 30 years ago, yet the role of sialylation in prion pathogenesis remains poorly understood. Recent years have witnessed extraordinary growth in interest in sialylation and established a critical role for sialic acids in host invasion and host-pathogen interactions. This review article summarizes current knowledge on the role of sialylation of the prion protein in prion diseases. First, we discuss the correlation between sialylation of PrP(Sc) glycans and prion infectivity and describe the factors that control sialylation of PrP(Sc). Second, we explain how glycan sialylation contributes to the prion replication barrier, defines strain-specific glycoform ratios, and imposes constraints for PrP(Sc) structure. Third, several topics, including a possible role for sialylation in animal-to-human prion transmission, prion lymphotropism, toxicity, strain interference, and normal function of PrP(C), are critically reviewed. Finally, a metabolic hypothesis on the role of sialylation in the etiology of sporadic prion diseases is proposed.

Keywords: amyloid; neuraminidase; prion disease; prions; sialic acid; sialylation; sialyltransferase; species barrier.

Figure 1

Structural diversity of Sias. Structures of two most common types of Sias, Neu5Ac, and Neu5Gc (A), and a diagram illustrating the differences in Sias synthesized in humans vs. non-human mammals (B). Structural diversity of Sias epitopes are achieved via naturally occurring modifications of Sias at 1-, 4-, 5-, 7-, 8-, or 9-carbon positions (C) and/or variations due to sulfation of galactose and N-acetylglucosamine that produce several Lewis glycoepitope families (D). Panel (D) shows only a small subset of possible sulfated variants.

Figure 2

Analysis of sialylation status of brain-, PMCAb-, and dsPMCAb-derived PrP^Sc for 263K strain using 2D western blots. Incubation time to disease and number of animals that developed clinical disease out of total number of animals is shown on the right. The data represented here is a modification of the figure from previously published manuscript (Katorcha et al., 2014).

Figure 3

A diagram illustrating mechanisms that control sialylation of PrP^Sc. (A) The sialylation status of PrP^C is controlled by STs in the trans-Golgi. (B) NEUs do not appear to affect the steady-state sialylation level of PrP^C, presumably because desialylated PrP^C is degraded rapidly. (C) Sialoglycoforms of PrP^C are recruitment into PrP^Sc selectively according to their sialylation status and in a strain-specific manner. (D) In SLOs, PrP^Sc is a subject of post-conversion sialylation by STs. Sias are shown as red diamonds.

Figure 4

Schematic diagram illustrating that PrP^Sc strains recruit PrP^C isoforms selectively according to PrP^C sialylation status. While strain #1 recruits sialoglycoforms of PrP^C without noticeable preferences, hypersialylated PrP^C are preferentially excluded from the strain the #2 and even more so from strain #3. As a result of strain-specific exclusion of highly sialylated PrP^C (illustrated by the 2D Western blots), the ratios of di- vs. mono-glycoforms within PrP^Sc changes in a strain-specific manner, as shown by 1D Western blots (right hand side). PrP^C molecules are shown as blue circles and sialic acid residues—as red diamonds.

Figure 5

N-linked glycans impose spatial constraints on folding patterns of PrP^Sc. Cross beta-sheet structures carrying tri-antennary N-glycans (shown in inset) on each neighboring beta-strand (A), or every second (B), third (C), or fourth (D) beta-strand. Polypeptide chains are represented in the tube form, whereas N-glycans are represented in the ball-and-stick form. Each PrP molecule with corresponding N-glycan is of a different color. Sialic acid residues are colored in red; N-glycan electrostatic surfaces are semi-transparent. To model the dimension of cross-beta structures, the parallel beta-sheet model was adapted from PDB database entry 2RNM, an NMR structure for HET-s(218–289) prion in its amyloid form (Wasmer et al., 2008). Stretches of seven amino acid residues are shows for each beta strand without any change to the atomic coordinates. The structure of a tri-antennary N-linked glycan was taken from PDB entry 3QUM, a crystal structure of human prostate specific antigen (PSA) (Stura et al., 2011). Both calculations of electrostatic surfaces and generation of images were performed with CCP4MG software.