Multifaceted Role of Sialylation in Prion Diseases

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.

Sialylation Controls Prion Fate in Vivo

“…In summary, the current study supports the new hypothesis that sialylation of PrP Sc controls its fate in an organism (27).…”

“…Glycoproteins or glycolipids that lack sialic acids at terminal positions serve as a "pathogen-associated molecular pattern" used by mammalian immune systems to recognize pathogens or asialoglycoproteins that need to be removed (25). Bearing in mind that sialylation serves as a molecular marker of self versus nonself, we proposed a hypothesis that sialylation determines the fate of prions in an organism (27) …”

Analyses of N‐linked glycans of PrPSc revealed predominantly 2,6‐linked sialic acid residues

“…Previously, we proposed that sialylation of PrP Sc glycans prevents the innate immune system and microglia from recognition of prions as potential pathogens and that sialylation controls PrP Sc fate in an organism [18][19][20][21]. In support of this hypothesis, we showed that PrP Sc with reduced sialylation levels does not induce prion disease in wild-type animals when administered via intracranial or intraperitoneal injections [19][20][21].…”

Complement Regulatory Protein Factor H Is a Soluble Prion Receptor That Potentiates Peripheral Prion Pathogenesis

“…Baskakov and colleagues convincingly demonstrated that sialylation status differs among prion strains (27,29), which could dictate fH binding. Katorcha et al reported that PrP Sc sialylation increased prion infectivity (28).…”

“…fH may bind sialylated PrP Sc and facilitate disease via the shuttling mechanism described above. Hepatocarcinoma cells utilize sialic acids to selectively adhere to secondary lymphoid organs (reviewed in 29). Perhaps fH aids sialylated prions infect lymphoid organs via a similar mechanism.…”