Sialylation Controls Prion Fate in Vivo

Abstract

Edited by Paul E. Fraser Prions or PrPSc are proteinaceous infectious agents that consist of misfolded, self-replicating states of a sialoglycoprotein called the prion protein or PrP C . The current work tests a new hypothesis that sialylation determines the fate of prions in an organism. To begin, we produced control PrP Sc from PrP C using protein misfolding cyclic amplification with beads (PMCAb), and also generated PrP Sc with reduced sialylation levels using the same method but with partially desialylated PrP C as a substrate (dsPMCAb (22,23). Sialylated glycans play an essential role in a broad range of cellular functions, but are especially important in immunity (24). Terminal sialic acid residues on the surface of mammalian cells act as a part of a "self-associated molecular pattern," providing molecular cues to the immune system for discriminating between "self," "altered self," or "non-self" (25, 26). 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

“…Our previous studies proposed that sialylation of PrP Sc N-linked glycans plays an important role in controlling the fate of prions in an organism [18,21]. In support of this hypothesis, we showed that animals inoculated with PrP Sc with reduced sialylation levels via intracranial or intraperitoneal routes lack any clinical or subclinical signs of prion disease, live healthy lives, and have undetectable levels of PrP Sc [19][20][21]. Considering that the sialylation status of PrP Sc is essential for determining its fate, it is important to investigate the cellular mechanisms that one can target for manipulating sialylation status of PrP C and PrP Sc .…”

“…Moreover, SLOs represent silent reservoirs of prion infection, where PrP Sc could hide undetected for a life-time while possibly imposing a high risk of transmission through blood donation [41, 42]. Our recent studies revealed that the sialylation status of PrP Sc was critical for its effective trafficking to SLOs [20]. Within several hours following peripheral exposure of mice to prions, PrP Sc with unaltered sialylation status was found to be sequestered by spleen and lymph nodes, whereas partially desialylated PrP Sc was found predominantly in liver [20].…”

“…Our recent studies revealed that the sialylation status of PrP Sc was critical for its effective trafficking to SLOs [20]. Within several hours following peripheral exposure of mice to prions, PrP Sc with unaltered sialylation status was found to be sequestered by spleen and lymph nodes, whereas partially desialylated PrP Sc was found predominantly in liver [20]. Notably, N-linked glycans sialylated via 2,6-linkages were shown to be responsible for directed trafficking and selective adhesion of hepatocarcinoma cells to SLOs [43, 44].…”

“…Moreover, we also showed that prion infectivity could be switched off and on in a reversible manner via removing and then reinstalling sialylation of N-linked glycans [19]. Finally, sialylation was found to be involved in PrP Sc trafficking and its sequestration by SLOs including spleen and lymph nodes [20]. As the sialylation status of PrP Sc is important to prion pathogenesis, dissecting the cellular mechanisms that control sialylation of PrP Sc might open new approaches for controlling or treating prion disease.…”

“…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]. Moreover, we also showed that prion infectivity could be switched off and on in a reversible manner via removing and then reinstalling sialylation of N-linked glycans [19].…”