Correction: Glycoform-Selective Prion Formation in Sporadic and Familial Forms of Prion Disease

Abstract

The four glycoforms of the cellular prion protein (PrP C ) variably glycosylated at the two N-linked glycosylation sites are converted into their pathological forms (PrP Sc ) in most cases of sporadic prion diseases. However, a prominent molecular characteristic of PrP Sc in the recently identified variably protease-sensitive prionopathy (VPSPr) is the absence of a diglycosylated form, also notable in familial Creutzfeldt-Jakob disease (fCJD), which is linked to mutations in PrP either from Val to Ile at residue 180 (fCJD V180I ) or from Thr to Ala at residue 183 (fCJD T183A ). Here we report that fCJD V180I , but not fCJD T183A , exhibits a proteinase K (PK)-resistant PrP (PrP res ) that is markedly similar to that observed in VPSPr, which exhibits a five-step ladder-like electrophoretic profile, a molecular hallmark of VPSPr. Remarkably, the absence of the diglycosylated PrP res species in both fCJD V180I and VPSPr is likewise attributable to the absence of PrP res glycosylated at the first N-linked glycosylation site at residue 181, as in fCJD T183A . In contrast to fCJD T183A , both VPSPr and fCJD V180I exhibit glycosylation at residue 181 on di-and monoglycosylated (mono181) PrP prior to PK-treatment. Furthermore, PrP V180I with a typical glycoform profile from cultured cells generates detectable PrP res that also contains the diglycosylated PrP in addition to mono-and unglycosylated forms upon PK-treatment. Taken together, our current in vivo and in vitro studies indicate that sporadic VPSPr and familial CJD V180I share a unique glycoform-selective prion formation pathway in which the conversion of diglycosylated and mono181 PrP C to PrP Sc is inhibited, probably by a dominant-negative effect, or by other co-factors.