Evidence for an association of prion protein and sphingolipid-mediated signaling.
The physiological function of the cellular prion protein (PrP(c)) is unclear. PrP(c) 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 PrP(c) and sphingolipid-associated signaling pathways. Using PrP(c)-wt and PrP(c)-k.o. hippocampal cell lines and mouse brains we showed higher activity of neutral and acid sphingomyelinase (SMase) in PrP(c)-k.o.-groups, while ceramide and sphingomyelin-levels were unchanged. Furthermore, despite lower basal expression levels of sphingosine kinase (SphK) in PrP(c)-k.o.-groups, the levels of its metabolite sphingosine-1-phosphate were increased, whereas S1P(3)-receptor expression was higher in PrP(c)-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 S1P(3) 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 PrP(c) is involved in sphingolipid-associated signaling, modulating pathways that exert anti-apoptotic functions, hence indicating that PrP(c) plays a role in neuroprotection.
Schmalzbauer
Rüdiger
R
Zentrum für Neuropathologie und Prionforschung, Ludwig-Maximilians-Universität München, München, Germany.
Eigenbrod
Sabina
S
Winoto-Morbach
Supandi
S
Xiang
Wei
W
Schütze
Stefan
S
Bertsch
Uwe
U
Kretzschmar
Hans A
HA
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018696:Neuroprotective Agents / Q000378:metabolism; D018621:PrPC Proteins / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013107:Sphingolipids / Q000502:physiology*
D051017:Apoptosis Regulatory Proteins; D018696:Neuroprotective Agents; D018621:PrPC Proteins; D013107:Sphingolipids