The prion protein in neuroimmune crosstalk

The cellular prion protein (PrPC) is a medium-sized glycoprotein, attached to the cell surface by a glycosylphosphatidylinositol anchor. PrPC is encoded by a single-copy gene, PRNP, which is abundantly expressed in the central nervous system and at lower levels in non-neuronal cells, including those of the immune system. Evidence from experimental knockout of PRNP in rodents, goats, and cattle and the occurrence of a nonsense mutation in goat that prevents synthesis of PrPC, have shown that the molecule is non-essential for life. Indeed, no easily recognizable phenotypes are associate with a lack of PrPC, except the potentially advantageous trait that animals without PrPC cannot develop prion disease. This is because, in prion diseases, PrPC converts to a pathogenic “scrapie” conformer, PrPSc, which aggregates and eventually induces neurodegeneration. In addition, endogenous neuronal PrPC serves as a toxic receptor to mediate prion-induced neurotoxicity. Thus, PrPC is an interesting target for treatment of prion diseases. Although loss of PrPC has no discernable effect, alteration of its normal physiological function can have very harmful consequences. It is therefore important to understand cellular processes involving PrPC, and research of this topic has advanced considerably in the past decade. Here, we summarize data that indicate the role of PrPC in modulating immune signaling, with emphasis on neuroimmune crosstalk both under basal conditions and during inflammatory stress.