The misfolding of the cellular prion protein (PrPC) causes fatal neurodegenerative diseases. Yet PrPC is highly conserved in mammals, suggesting that it exerts beneficial functions preventing its evolutionary elimination. Ablation of PrPC in mice results in well-defined structural and functional alterations in the peripheral nervous system. Many additional phenotypes were ascribed to the lack of PrPC, but some of these were found to arise from genetic artifacts of the underlying mouse models. Here, we revisit the proposed physiological roles of PrPC in the central and peripheral nervous systems and highlight the need for their critical reassessment using new, rigorously controlled animal models.
The cellular prion protein (PrPC) is a cell surface protein expressed in a variety of different organs and tissues with high expression levels in the central and peripheral nervous systems . It is mainly known for its infamous role in prion diseases, where its misfolding and aggregation cause inevitably fatal neurodegenerative conditions . Prion diseases are transmissible and misfolded prion protein (PrPSc) is—according to the “protein-only hypothesis’”—the only disease-causing agent . Under this view, it is puzzling that a protein underlying such severe diseases is highly conserved throughout mammals . This suggests the existence of distinct benefits and, potentially, important physiological functions.
A definitive, fully satisfactory understanding of the physiological function of PrPC has been lacking for a long time. Very recently, we identified a native function of PrPC in the peripheral nervous system and the underlying mechanism of that function . However, PrPC is also highly expressed in the central nervous system (CNS) and its biological activity there is still far from being clear. This review will focus on the proposed roles of cellular prion protein in the central and peripheral nervous systems.