The biological function of the cellular prion protein: an update

The misfolding of the cellular prion protein (PrP(C)) causes fatal neurodegenerative diseases. Yet PrP(C) is highly conserved in mammals, suggesting that it exerts beneficial functions preventing its evolutionary elimination. Ablation of PrP(C) in mice results in well-defined structural and functional alterations in the peripheral nervous system. Many additional phenotypes were ascribed to the lack of PrP(C), but some of these were found to arise from genetic artifacts of the underlying mouse models. Here, we revisit the proposed physiological roles of PrP(C) in the central and peripheral nervous systems and highlight the need for their critical reassessment using new, rigorously controlled animal models.