Abstract
Mammalian prion or PrPSc is a proteinaceous infectious agent that consists of a misfolded, self-replicating state of a sialoglycoprotein called the prion protein, or PrPC. 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 PrPSc glycans and prion infectivity and describe the factors that control sialylation of PrPSc. Second, we explain how glycan sialylation contributes to the prion replication barrier, defines strain-specific glycoform ratios, and imposes constraints for PrPSc 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 PrPC, are critically reviewed. Finally, a metabolic hypothesis on the role of sialylation in the etiology of sporadic prion diseases is proposed.
Highlights
Prions or PrPSc are proteinaceous infectious agents that consist of misfolded, self-replicating states of a sialoglycoprotein called the prion protein or PrPC (Prusiner, 1982; Legname et al, 2004)
A number of amyloidogenic proteins or peptides, including Aβ, α-synuclein, tau, Sialylation in Prion Diseases huntingtin, which are associated with a range of age-dependent neurodegenerative diseases, can spread from cell to cell or be transmitted from animal to animal or human to animal in a prion-like fashion (Soto et al, 2006; Walker and Jucker, 2015)
Recent studies suggest that sialylation of PrPSc controls its fate in an organism and the outcomes of prion disease
Summary
Sialic acids (Sias) are a family of 9-carbon containing acidic monosaccharides that are found in terminal positions of Nand O-linked glycans of glycoproteins or glycolipids (Figure 1A) (Varki, 1999). Bearing in mind that sialylation controls the height of the conformational transition barrier (Katorcha et al, 2015b), it is reasonable to propose that the first spontaneous PrPC-to-PrPSc conversion events have a higher chance of occurring in brain areas that express PrPC with glycans of small sizes and reduced sialylation levels and/or in individuals with deficient sialylation substrate. The relative ranking of the two types of CJD with respect to sialylation is consistent with the hypothesis that sialylation is important for effective trafficking of PrPSc to SLOs. Interaction of PrPSc particles with PrPC molecules anchored via GPI on the cell surface is believed to be important for triggering toxic signals (Solforosi et al, 2004; Sonati et al, 2012). The defect in polysialylation was found to be due to impairment in expression of sialyltransferase ST8Sia, which is responsible for polysialylating glycoproteins
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