Evidence for an association of prion protein and sphingolipid-mediated signaling

Abstract

The physiological function of the cellular prion protein (PrPc) is unclear. PrPc associates with lipid rafts, highly glycolipid-rich membrane domains containing a large variety of signaling molecules, e.g., sphingolipids (SL). In this study, we investigated possible connections between PrPc and sphingolipid-associated signaling pathways. Using PrP c-wt and PrPc-k.o. hippocampal cell lines and mouse brains we showed higher activity of neutral and acid sphingomyelinase (SMase) in PrPc-k.o.-groups, while ceramide and sphingomyelin-levels were unchanged. Furthermore, despite lower basal expression levels of sphingosine kinase (SphK) in PrPc-k.o.-groups, the levels of its metabolite sphingosine-1-phosphate were increased, whereas S1P3-receptor expression was higher in PrPc-wt-groups again. In addition, we detected enhanced activity of phospholipase D1, an enzyme that seems to be suitable to act as a connector between the S1P3 receptor and continuative signaling. Finally, evidence for an impact on downstream signaling cascades, especially activation of the PI3K/Akt pathway, was found. In summary, our data suggest that PrPc is involved in sphingolipid-associated signaling, modulating pathways that exert anti-apoptotic functions, hence indicating that PrPc plays a role in neuroprotection. © 2008 The Authors.