Abstract
Prions or PrP(Sc) are proteinaceous infectious agents that consist of misfolded, self-replicating states of the prion protein or PrP(C) PrP(C) is posttranslationally modified with N-linked glycans and a sialylated glycosylphosphatidylinositol (GPI) anchor. Conformational conversion of PrP(C) gives rise to glycosylated and GPI-anchored PrP(Sc) The question of the sialylation status of GPIs within PrP(Sc) has been controversial. Previous studies that examined scrapie brains reported that both sialo- and asialo-GPIs were present in PrP(Sc), with the majority being asialo-GPIs. In contrast, recent work that employed cultured cells claimed that only PrP(C) with sialylo-GPIs could be recruited into PrP(Sc), whereas PrP(C) with asialo-GPIs inhibited conversion. To resolve this controversy, we analyzed the sialylation status of GPIs within PrP(Sc) generated in the brain, spleen, or cultured N2a or C2C12 myotube cells. We found that recruiting PrP(C) with both sialo- and asialo-GPIs is a common feature of PrP(Sc) The mixtures of sialo- and asialo-GPIs were observed in PrP(Sc) universally regardless of prion strain as well as host, tissue, or type of cells that produced PrP(Sc) Remarkably, the proportion of sialo- versus asialo-GPIs was found to be controlled by host, tissue, and cell type but not prion strain. In summary, this study found no strain-specific preferences for selecting PrP(C) with sialo- versus asialo-GPIs. Instead, this work suggests that the sialylation status of GPIs within PrP(Sc) is regulated in a cell-, tissue-, or host-specific manner and is likely to be determined by the specifics of GPI biosynthesis.
Highlights
Prions or PrPSc2 are proteinaceous infectious agents that consist of misfolded, self-replicating states of a sialoglycoprotein called the prion protein or PrPC [1, 2]
Experiments using primary neuronal cultures suggested that toxicity triggered by PrPSc is dependent on the sialylation status of the GPI anchor within PrPC, as clustering of PrPC molecules with sialylated GPIs led to activation of cytoplasmic phospholipase A2 and synapse damage [31]
GPI Anchors of Brain-derived Mouse PrPSc Consist of Sialylated and Asialylated Forms—To assess the sialylation status of GPI anchors, PrPSc was denatured into monomers, and individual PrP molecules were analyzed using two-dimensional gel electrophoresis followed by Western blotting
Summary
The endoplasmic reticulum and Golgi [34, 35]. Because sialyltransferases are localized in the Golgi [36], sialylation of GPIs presumably occurs in the Golgi after their attachment to proteins. A recent work by Bate et al [37] claimed that only PrPC with sialylated GPIs could be recruited into PrPSc, whereas PrPC with asialo-GPIs inhibits conversion of PrPC with sialo-GPIs into PrPSc. To resolve the controversy, we analyzed the sialylation status of GPIs within PrPSc of five prion strains from two hosts. This study reports that PrPSc can recruit PrPC with both sialo- and asialo-GPIs, as the mixtures of sialoand asialo-GPIs were observed universally regardless of prion strain or host, tissue, or cell type in which PrPSc was generated. The proportion of sialo forms of GPIs was variable and depended on the host, tissue, and cell type but not prion strain These findings suggest that the proportion of the two sialo forms of GPIs within PrPSc is determined by cell- or tissue-specific rates of synthesis of sialo-GPIs but not strainspecific structural constraints
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