PRNP and prion disease: While, on the one hand, it might confer protection against prion diseases as the reduction of PrPC at the cellular surface would reduce the substrate for PrPC-to-PrPSc conversion, and shed PrPC may impair this misfolding by binding to extracellular prion seeds (37, 38, 39, 40); on the other hand, it could facilitate prion spread and plaque formation by generating anchorless diffusible prions (32, 41, 42, 43, 44, 45, 46).