title: Biochemical fingerprints of prion diseases: scrapie prion protein in human prion diseases that share prion genotype and type.
abstract: The phenotype of human prion diseases is influenced by the prion protein (PrP) genotype as determined by the methionine (M)/valine (V) polymorphism at codon 129, the scrapie PrP (PrPSc) type and the etiology. To gain further insight into the mechanisms of phenotype determination, we compared two-dimensional immunoblot profiles of detergent insoluble and proteinase K-resistant PrP species in a type of sporadic Creutzfeldt-Jakob disease (sCJDMM2), variant CJD (vCJD) and sporadic fatal insomnia (sFI). Full-length and truncated PrP forms present in the insoluble fractions were also separately analyzed. These three diseases were selected because they have the same M/M PrP genotype at codon 129 and the same type 2 PrPSc, but different etiologies, also sCJDMM2 and sFI are sporadic, whereas vCJD is acquired by infection. We observed minor differences in the PrP detergent-insoluble fractions between sCJDMM2 and vCJD, although both differ in the corresponding fractions from sFI. We detected more substantial heterogeneity between sCJDMM2 and vCJD in the two-dimensional blots of the proteinase K-resistant PrP fraction suggesting that different PrP species are selected for conversion to proteinase K-resistant PrP in sCJDMM2 and vCJD. These differences are mostly, but not exclusively, due to variations in the type of the N-linked glycans. We also show that the over-representation of the highly glycosylated forms distinctive of the proteinase K-resistant PrPSc of vCJD in one-dimensional blots is due to differences in both the amount and the natures of the glycans. Overall, these findings underline the complexity of phenotypic determination in human prion diseases.
authors.affiliation: Division of Neuropathology, Case Western Reserve University, Cleveland, Ohio 44120, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Pan
authors.forename: Ruliang
authors.initials: R
authors.lastname: Li
authors.forename: Shin-Chung
authors.initials: SC
authors.lastname: Kang
authors.forename: Manuela
authors.initials: M
authors.lastname: Pastore
authors.forename: Boon-Seng
authors.initials: BS
authors.lastname: Wong
authors.forename: James
authors.initials: J
authors.lastname: Ironside
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Gambetti
authors.forename: Man-Sun
authors.initials: MS
authors.lastname: Sy
mesh_terms: D015415:Biomarkers / Q000032:analysis; D015180:Electrophoresis, Gel, Two-Dimensional / Q000379:methods; D005838:Genotype; D006801:Humans; D010449:Peptide Mapping / Q000379:methods*; D018620:PrPSc Proteins / Q000032:analysis / Q000378:metabolism*; D017096:Prion Diseases / Q000235:genetics*
chemical_list: D015415:Biomarkers; D018620:PrPSc Proteins