Mutant PrPCJD prevails over wild-type PrPCJD in the brain of V210I and R208H genetic Creutzfeldt-Jakob disease patients.

Abstract

Creutzfeldt-Jakob disease (CJD) is a neurodegenerative disorder characterized by the deposition of the pathological conformer (PrP(CJD)) of the host encoded cellular prion protein (PrP(C)). In genetic CJD associated with V210I or R208H PrP substitutions, the pathogenic role of mutant residues is still poorly understood. To understand how V210I or R208H PrP mutations facilitate the development of the disease, we determined by mass spectrometry the quantitative ratio of mutant/wild-type PrP(CJD) allotypes in brains from affected subjects. We found that the mutant PrP(CJD) allotypes moderately exceeds of 2- or 3-fold the amount of the wild-type counterpart suggesting that these mutations mainly exert their pathogenic effect on the onset of the pathogenic cascade. Different mechanisms can be hypothesized to explain the pathogenic role of mutant residues: V210I and R208H substitutions can increase the concentration of PrP(C) and the probability to form insoluble aggregates, or they may facilitate the formation of pathological intermediates, or, alternatively, they may increase the affinity for ligands that are involved in the initial phases of PrP(CJD) formation and aggregation. Whatever the mechanism, the enrichment found for the mutated PrP(CJD) species indicates that these altered structures are more prone, with respect to the non-mutated ones, to be captured in the polymerization process either at the onset or during the development of the disease.

• Authors: Franco Cardone, Serena Principe, Maria Eugenia Schininà, Bruno Maras, Sabina Capellari, Piero Parchi, Silvio Notari, Laura Di Francesco, Anna Poleggi, Roberta Galeno, Ramona Vinci, Vittorio Mellina, Susanna Almonti, Anna Ladogana, Maurizio Pocchiari
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 454 Issue 2 Pg. 289-94 (Nov 14 2014) ISSN: 1090-2104 [Electronic] United States
• PMID: 25450391 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• PrPSc Proteins

Topics

• Brain (metabolism, pathology)
• Creutzfeldt-Jakob Syndrome (genetics, pathology)
• Genotype
• Humans
• Mass Spectrometry
• Point Mutation
• PrPSc Proteins (analysis, genetics)
• Protein Folding