Sialic Acid on the Glycosylphosphatidylinositol Anchor Regulates PrP-mediated Cell Signalling and Prion Formation [Cell Biology]

November 9th, 2015 by Bate, C., Nolan, W., Williams, A.

The prion diseases occur following the conversion of the cellular prion protein (PrPC) into disease-related isoforms (PrPSc). In this study the role of the glycosylphosphatidylinositol (GPI) anchor attached to PrPC in prion formation was examined using a cell painting technique. PrPSc formation in two prion-infected neuronal cell lines (ScGT1 and ScN2a cells), and in scrapie-infected primary cortical neurons, was increased following the introduction of PrPC. In contrast, PrPC containing a GPI anchor from which the sialic acid had been removed (desialylated PrPC) was not converted to PrPSc. Furthermore, the presence of desialylated PrPC inhibited the production of PrPSc within prion-infected cortical neurons, ScGT1 and ScN2a cells. The membrane rafts surrounding desialylated PrPC contained greater amounts of sialylated gangliosides and cholesterol than membrane rafts surrounding PrPC. Desialylated PrPC was less sensitive to cholesterol depletion than PrPC and was not released from cells by treatment with glimepiride The presence of desialylated PrPC in neurons caused the dissociation of cytoplasmic phospholipase A2 (cPLA2) from PrP-containing membrane rafts and reduced the activation of cPLA2. These findings show that the sialic acid moiety of the GPI attached to PrPC modifies local membrane microenvironments that are important in PrP-mediated cell signalling and PrPSc formation. These results suggest that pharmacological modification of GPI glycosylation might constitute a novel therapeutic approach to prion diseases.