title: Phenotypic heterogeneity in inherited prion disease (P102L) is associated with differential propagation of protease-resistant wild-type and mutant prion protein.
abstract: Inherited prion diseases are caused by PRNP coding mutations and display marked phenotypic heterogeneity within families segregating the same pathogenic mutation. A proline-to-leucine substitution at prion protein (PrP) residue 102 (P102L), classically associated with the Gerstmann-Sträussler-Scheinker (GSS) phenotype, also shows marked clinical and pathological heterogeneity, including patients with a Creutzfeldt-Jakob disease (CJD) phenotype. To date, this heterogeneity has been attributed to temporal and spatial variance in the propagation of distinct protease-resistant (PrP(Sc)) isoforms of mutant PrP. Here, using a monoclonal antibody that recognizes wild-type PrP, but not PrP 102L, we reveal a spectrum of involvement of wild-type PrP(Sc) in P102L individuals. PrP(Sc) isoforms derived from wild-type and mutant PrP are distinct both from each other and from those seen in sporadic and acquired CJD. Such differential propagation of disease-related isoforms of wild-type PrP and PrP 102L provides a molecular mechanism for generation of the multiple clinicopathological phenotypes seen in inherited prion disease.
authors.affiliation: MRC Prion Unit and Department of Neurodegenerative Disease, Institute of Neurology, University College London, National Hospital for Neurology and Neurosurgery Queen Square, London, UK.
authors.forename: Jonathan D F
authors.initials: JD
authors.lastname: Wadsworth
authors.forename: Susan
authors.initials: S
authors.lastname: Joiner
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Linehan
authors.forename: Sharon
authors.initials: S
authors.lastname: Cooper
authors.forename: Caroline
authors.initials: C
authors.lastname: Powell
authors.forename: Gary
authors.initials: G
authors.lastname: Mallinson
authors.forename: Jennifer
authors.initials: J
authors.lastname: Buckell
authors.forename: Ian
authors.initials: I
authors.lastname: Gowland
authors.forename: Emmanuel A
authors.initials: EA
authors.lastname: Asante
authors.forename: Herbert
authors.initials: H
authors.lastname: Budka
authors.forename: Sebastian
authors.initials: S
authors.lastname: Brandner
authors.forename: John
authors.initials: J
authors.lastname: Collinge
mesh_terms: D000328:Adult; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D008875:Middle Aged; D050505:Mutant Proteins / Q000032:analysis* / Q000276:immunology; D009154:Mutation; D010447:Peptide Hydrolases; D010641:Phenotype; D017096:Prion Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000635:transmission; D011328:Prions / Q000032:analysis / Q000235:genetics* / Q000276:immunology; D020033:Protein Isoforms / Q000235:genetics / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D050505:Mutant Proteins; D011328:Prions; D020033:Protein Isoforms; D010447:Peptide Hydrolases