NR AUOX
AU Wadsworth,J.D.F.; Joiner,S.; Linehan,J.M.; Cooper,S.; Powell,C.; Mallinson,G.; Buckell,J.; Gowland,I.; Asante,E.A.; Budka,H.; Brandner,S.; Collinge,J.
TI Phenotypic heterogeneity in inherited prion disease (P102L) is associated with differential propagation of protease-resistant wild-type and mutant prion protein
QU Brain: A Journal of Neurology 2006 Jun; 129(6): 1557-69
PT journal article
AB 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 (PrPsc) 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 PrPsc in P102L individuals. PrPsc 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.
MH Adult; Animals; Antibodies, Monoclonal/immunology; Brain/metabolism/pathology; Enzyme-Linked Immunosorbent Assay/methods; Humans; Mice; Mice, Transgenic; Microscopy, Confocal; Middle Aged; Mutant Proteins/*analysis/immunology; Mutation; Peptide Hydrolases; Phenotype; Prion Diseases/*genetics/metabolism/pathology/transmission; Prions/analysis/*genetics/immunology; Protein Isoforms/genetics/immunology; Research Support, Non-U.S. Gov't
AD Jonathan D. F. Wadsworth, Susan Joiner, Jacqueline M. Linehan, Sharon Cooper, Caroline Powell, Gary Mallinson, Jennifer Buckell, Ian Gowland, Emmanuel A. Asante, Sebastian Brandner, John Collinge (j.collinge@prion.ucl.ac.uk), MRC Prion Unit and Department of Neurodegenerative Disease, Institute of Neurology, University College London, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK; Herbert Budka, Institute of Neurology, Medical University Vienna, Wien, Austria
SP englisch
PO England