The PTM profile of PrPC varies according to the cell context due to cell-type specific equipment in sialyltransferases, glycosidases, α-secretases, etc. Specific PTM combinations at the proximal level of PrPC in defined brain areas and peripheral tissues would thus sustain the regio-selective emergence of peculiar prion strains, their accumulation, tropism toward definite neuronal cell types, and the susceptibility of specific neuronal populations to respond to prion strain infection, ultimately leading to neurodegeneration. This evidence concerns the gene PRNP and infection.