Briefly, (i) presence of extracellular PrPSc does not lead to prion-induced neurodegeneration in the absence of PrPC on neurons [51, 52], (ii) cells expressing either anchorless PrP or PrP with a transmembrane domain instead of the GPI-anchor are resistant to prion infection [17, 18, 53], and (iii) prion-infected transgenic mice expressing low amounts of anchorless PrP do not show clinical symptoms of prion disease despite high titers of infectivity and high levels of PrPSc [21, 54]. Here, PRNP is linked to prion disease.