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

Although the cellular prion protein (PrP$^{C}$ ) is concentrated at synapses, the factors that target PrP$^{C}$ to synapses are not understood. Here we demonstrate that exogenous PrP$^C$ was rapidly targeted to synapses in recipient neurons derived from Prnp knockout$^{(0/0)}$ mice. The targeting of PrP$^C$ to synapses was dependent upon both neuronal cholesterol concentrations and the lipid and glycan composition of its glycosylphosphatidylinositol (GPI) anchor. Thus, the removal of either an acyl chain or sialic acid from the GPI anchor reduced the targeting of PrP$^C$ to synapses. Isolated GPIs (derived from PrP$^C$ ) were also targeted to synapses as was IgG conjugated to these GPIs. The removal of sialic acid from GPIs prevented the targeting of either the isolated GPIs or the IgG-GPI conjugate to synapses. Competition studies showed that pretreatment with sialylated GPIs prevented the targeting of PrP$^C$ to synapses. These results are consistent with the hypothesis that the sialylated GPI anchor attached to PrP$^C$ acts as a synapse homing signal.This work was supported by the European Commission FP6 “Neuroprion” – Network of Excellence.This is the author accepted manuscript. The final version is available from the American Society for Biochemistry and Molecular Biology via http://dx.doi.org/10.1074/jbc.M116.73111