EFFECT OF THE D178N MUTATION AND THE CODON-129 POLYMORPHISM ON THE METABOLISM OF THE PRION PROTEIN

Prion diseases are thought to be caused by the conversion of the norma l, or cellular, prion protein (PrPC) into an abnormal protease-resista nt conformation (PrPres). There are three familial forms of human prio n disease, Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Schei nker syndrome, and fatal familial insomnia (FFI) which are all express ed at advanced age despite the congenital presence of the mutant prion protein (PrPM). The cellular mechanisms that result in the age-depend ent conversion of PrPM into PrPres and the unique phenotypes associate d with each PrPM are unknown. FFI and a familial type of Creutzfeldt-J akob disease (CJD(178)), share the D178N mutation in the PrP gene but have distinct phenotypes linked to codon 129, the site of a methionine /valine polymorphism (129M/V). We analyzed PrP processing in cells tra nsfected with constructs reproducing the FFI and CJD(178) genotypes. T he D178N mutation results in instability of the mutant PrP which is pa rtially corrected by N-glycosylation. Hence, only the glycosylated for ms of PrPM reach the cell surface whereas the unglycosylated form is d egraded. The unglycosylated PrPM is also under-represented in the brai n of FFI patients validating the cell model. These results offer new i nsight into the effect of the D178N mutation on the metabolism of the prion protein.