title: Allelic origin of the abnormal prion protein isoform in familial prion diseases.
abstract: The hallmark of prion diseases is the presence of an aberrant isoform of the prion protein (PrP(res)) that is insoluble in nondenaturing detergents and resistant to proteases. We investigated the allelic origin of PrP(res) in brains of subjects heterozygous for the D178N mutation linked to fatal familial insomnia (FFI) and a subtype of Creutzfeldt-Jakob disease (CJD178), as well as for insertional mutations associated with another CJD subtype. We found that in FFI and CJD178 subjects, only mutant PrP was detergent-insoluble and protease-resistant. Therefore, PrP(res) derives exclusively from the mutant allele carrying the D178N mutation. In contrast, in the CJD subtype harboring insertional mutations, wild-type PrP was also detergent-insoluble and likely to be protease-resistant. Our findings indicate that the participation of the wild-type PrP in the formation of PrP(res) depends on the type of mutations, providing an insight into the molecular mechanisms underlying the phenotypic heterogeneity in familial prion diseases.
authors.affiliation: Division of Neuropathology, Institute of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA.
authors.forename: S G
authors.initials: SG
authors.lastname: Chen
authors.forename: P
authors.initials: P
authors.lastname: Parchi
authors.forename: P
authors.initials: P
authors.lastname: Brown
authors.forename: S
authors.initials: S
authors.lastname: Capellari
authors.forename: W
authors.initials: W
authors.lastname: Zou
authors.forename: E J
authors.initials: EJ
authors.lastname: Cochran
authors.forename: C L
authors.initials: CL
authors.lastname: Vnencak-Jones
authors.forename: J
authors.initials: J
authors.lastname: Julien
authors.forename: C
authors.initials: C
authors.lastname: Vital
authors.forename: J
authors.initials: J
authors.lastname: Mikol
authors.forename: E
authors.initials: E
authors.lastname: Lugaresi
authors.forename: L
authors.initials: L
authors.lastname: Autilio-Gambetti
authors.forename: P
authors.initials: P
authors.lastname: Gambetti
mesh_terms: D000483:Alleles; D007562:Creutzfeldt-Jakob Syndrome / Q000145:classification / Q000235:genetics; D003902:Detergents; D010450:Endopeptidases; D006579:Heterozygote; D006801:Humans; D009154:Mutation; D010449:Peptide Mapping; D010641:Phenotype; D017354:Point Mutation; D017096:Prion Diseases / Q000235:genetics*; D011328:Prions / Q000235:genetics* / Q000302:isolation & purification; D007319:Sleep Initiation and Maintenance Disorders / Q000235:genetics; D012995:Solubility
chemical_list: D003902:Detergents; D011328:Prions; D010450:Endopeptidases