Prions are a novel class of infectious pathogens that cause a group of fatal prion diseases in which the benign cellular form of the prion protein (PrP C) is transformed into the disease-related scrapie variant (PrP SC). The two PrP isoforms differ in their structure and resistance to degradation. The molecular mechanism by which the PrP SC is formed and causes infectivity or neurodegeneration is not known. In a compelling and emerging view, posttranslational modifications (or the lack thereof) play roles in the transformation of PrP C to PrP SC. Human PrP contains two consensus sites for N-linked glycosylation, at Asn181 and Asn197. From the functional standpoint, glycosylation can modify either the conformation of PrP C, or the stability of PrPSC and, hence, the rate of PrPSC clearance. So far the NMR structures of only recombinant, non-glycosylated prions are known, while the structure of the glycosylated form is estimated by molecular modeling. A number of native amino acid mutations in PrP can be mapped near the glycosylation sites. Normal prion protein has been demonstrated to be a copper binding protein, and increasing evidence has shown correlation between the level of PrP expression and tolerance to oxidative stress. Moreover, histochemistry for nitrotyrosine is used for detection of neuronal labeling, a sign of a peroxynitrite-mediated neuronal degradation and a marker for nitrative stress in scrapie-infected mouse brains. It is an intriguing proposition that the post translational modifications alone, or in combination with amino acid changes, play dominant roles in the pathogenic transformation of PrPC to PrPSC.
Keywords: Post-Translational, Prion Proteins, GLYCOSYLATION, ASPARAGINE, encephalopathy, Creutzfeldt-Jacob disease, Glycosyl-phosphatidyl-inositol, Sodium dodecyl, Superoxide dismutase
Rights & PermissionsPrintExport