Sialic Acid within the Glycosylphosphatidylinositol Anchor Targets the Cellular Prion Protein to Synapses

Bate, Clive; Nolan, William; McHale-Owen, Harriet; Williams, Alun

doi:10.1074/jbc.m116.731117

Cited by 20 publications

(14 citation statements)

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“…Moreover, sialylation status of GPIs was found to modify the local environment of PrP C where the greater amounts of sialylated gangliosides and cholesterol were found in rafts surrounding PrP C with asialo-GPIs relative to PrP C with sialo-GPIs (Bate et al, 2016b ). In addition, sialo-GPIs were found to target exogenous PrP C to synapses of neurons derived from the prion protein knockout mice (Bate et al, 2016a ). Because cell painting technique was used in aforementioned studies, the questions whether the conclusions reached by using PrP C exogenously added to cells are valid for PrP C expressed by a cell or in animals have to be addressed.…”

Section: Sialylation Of Gpi Anchormentioning

confidence: 99%

Multifaceted Role of Sialylation in Prion Diseases

Baskakov

Katorcha

2016

Front. Neurosci.

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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.

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Section: Sialylation Of Gpi Anchormentioning

confidence: 99%

Multifaceted Role of Sialylation in Prion Diseases

Baskakov

Katorcha

2016

Front. Neurosci.

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“…Notably, we showed that by changing the GPI-SS, the biochemical composition of the GPI-anchor is altered, presenting with a loss of the sialic acid usually present in the GPI-anchor of PrP C . It has recently been shown that the sialic acid in the GPI-anchor of PrP C has a role in the synaptic targeting of PrP C in cultured cells [13]. Thus, when sialic acid from exogenously administered GPI-anchored PrP is depleted, or the lipid moiety is changed, PrP C still partitions in DRMs but is no longer targeted to synapses.…”

Section: Discussionmentioning

confidence: 99%

“…Most recently, Bate et al . demonstrated that sialylation of the PrP C GPI-anchor plays a role in its synaptic targeting [13]. Although it has already been shown that the GPI-SS influences intracellular sorting in vitro , how differences in the GPI-SS impact on the GPI-anchor composition in neuronal cells or in the brain, has not been investigated yet.…”

Section: Introductionmentioning

confidence: 99%

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GPI-anchor signal sequence influences PrPC sorting, shedding and signalling, and impacts on different pathomechanistic aspects of prion disease in mice

et al. 2019

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The cellular prion protein (PrPC) is a cell surface glycoprotein attached to the membrane by a glycosylphosphatidylinositol (GPI)-anchor and plays a critical role in transmissible, neurodegenerative and fatal prion diseases. Alterations in membrane attachment influence PrPC-associated signaling, and the development of prion disease, yet our knowledge of the role of the GPI-anchor in localization, processing, and function of PrPC in vivo is limited We exchanged the PrPC GPI-anchor signal sequence of for that of Thy-1 (PrPCGPIThy-1) in cells and mice. We show that this modifies the GPI-anchor composition, which then lacks sialic acid, and that PrPCGPIThy-1 is preferentially localized in axons and is less prone to proteolytic shedding when compared to PrPC. Interestingly, after prion infection, mice expressing PrPCGPIThy-1 show a significant delay to terminal disease, a decrease of microglia/astrocyte activation, and altered MAPK signaling when compared to wild-type mice. Our results are the first to demonstrate in vivo, that the GPI-anchor signal sequence plays a fundamental role in the GPI-anchor composition, dictating the subcellular localization of a given protein and, in the case of PrPC, influencing the development of prion disease.

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“…The terminal ends of complex N-linked glycoproteins are composed of sialic acids, which serve several functions, such as altering susceptibility of proteins to proteolysis (14)(15)(16)(17). NA, also known as sialidase, has frequently been used to catalyze the hydrolysis of terminal sialic acid residues from the oligosaccharides on cell surfaces (14)(15)(16)(17). To examine whether sialic acids of the oligosaccharides play a role in the protection of hERG channels against proteolytic digestion by PK, we examined PK cleavage of NA-treated hERG-HEK cells.…”

Section: Sialic Acids Of Oligosaccharides Do Not Affect the Glycosylamentioning

confidence: 99%

Glycosylation stabilizes hERG channels on the plasma membrane by decreasing proteolytic susceptibility

et al. 2018

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The human ether-a-go-go related gene ( hERG)-encoded channel hERG undergoes N-linked glycosylation at position 598, which is located in the unusually long S5-pore linker of the channel. In other work we have demonstrated that hERG is uniquely susceptible to proteolytic cleavage at the S5-pore linker by proteinase K (PK) and calpain (CAPN). The scorpion toxin BeKm-1, which binds to the S5-pore linker of hERG, protects hERG from such cleavage. In the present study, our data revealed that, compared with normal glycosylated hERG channels, nonglycosylated hERG channels were significantly more susceptible to cleavage by extracellular PK. Furthermore, the protective effect of BeKm-1 on hERG from PK-cleavage was lost when glycosylation of hERG was inhibited. The inactivation-deficient mutant hERG channels S620T and S631A were resistant to PK cleavage, and inhibition of glycosylation rendered both mutants susceptible to PK cleavage. Compared with normal glycosylated channels, nonglycosylated hERG channels were also more susceptible to cleavage mediated by CAPN, which was present in the medium of human embryonic kidney cells under normal culture conditions. Inhibition of CAPN resulted in an increase of nonglycosylated hERG current. In summary, our results revealed that N-linked glycosylation protects hERG against protease-mediated degradation and thus contributes to hERG channel stability on the plasma membrane.-Lamothe, S. M., Hulbert, M., Guo, J., Li, W., Yang, T., Zhang, S. Glycosylation stabilizes hERG channels on the plasma membrane by decreasing proteolytic susceptibility.

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Sialic Acid within the Glycosylphosphatidylinositol Anchor Targets the Cellular Prion Protein to Synapses

Cited by 20 publications

References 50 publications

Multifaceted Role of Sialylation in Prion Diseases

Multifaceted Role of Sialylation in Prion Diseases

GPI-anchor signal sequence influences PrPC sorting, shedding and signalling, and impacts on different pathomechanistic aspects of prion disease in mice

Glycosylation stabilizes hERG channels on the plasma membrane by decreasing proteolytic susceptibility

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