title: 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.
authors.affiliation: Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America.
authors.forename: Xiangzhu
authors.initials: X
authors.lastname: Xiao
authors.forename: Jue
authors.initials: J
authors.lastname: Yuan
authors.forename: Stéphane
authors.initials: S
authors.lastname: Haïk
authors.forename: Ignazio
authors.initials: I
authors.lastname: Cali
authors.forename: Yian
authors.initials: Y
authors.lastname: Zhan
authors.forename: Mohammed
authors.initials: M
authors.lastname: Moudjou
authors.forename: Baiya
authors.initials: B
authors.lastname: Li
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Laplanche
authors.forename: Hubert
authors.initials: H
authors.lastname: Laude
authors.forename: Jan
authors.initials: J
authors.lastname: Langeveld
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Gambetti
authors.forename: Tetsuyuki
authors.initials: T
authors.lastname: Kitamoto
authors.forename: Qingzhong
authors.initials: Q
authors.lastname: Kong
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Brandel
authors.forename: Brian A
authors.initials: BA
authors.lastname: Cobb
authors.forename: Robert B
authors.initials: RB
authors.lastname: Petersen
authors.forename: Wen-Quan
authors.initials: WQ
authors.lastname: Zou
mesh_terms: D001921:Brain / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D007562:Creutzfeldt-Jakob Syndrome / Q000378:metabolism; D019286:Endopeptidase K / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D011134:Polysaccharides / Q000737:chemistry; D017096:Prion Diseases / Q000378:metabolism*; D011328:Prions / Q000737:chemistry / Q000378:metabolism*; D059748:Proteolysis; D014633:Valine / Q000737:chemistry
chemical_list: D011134:Polysaccharides; D011328:Prions; D019286:Endopeptidase K; D014633:Valine