Moreover, it (ii) challenges both, toxic CPP-like and protective antiprion effects of cytosolic N1 with uncleaved signal peptides (N1-SP), (iii) questions a relevant role of cytosolic prions in prion diseases, and (iv) highlights important aspects to be considered when investigating the α-cleavage of PrPC or devising N1-based therapeutic approaches in the future. This evidence concerns the gene PRNP and prion disease.