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

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

Research output: Contribution to journalArticlepeer-review

Abstract

Creutzfeldt-Jakob disease (CJD) is a neurodegenerative disorder characterized by the deposition of the pathological conformer (PrPCJD) of the host encoded cellular prion protein (PrPC). 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 PrPCJD allotypes in brains from affected subjects. We found that the mutant PrPCJD 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 PrPC 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 PrPCJD formation and aggregation. Whatever the mechanism, the enrichment found for the mutated PrPCJD 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.

Original languageEnglish
Pages (from-to)289-294
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume454
Issue number2
DOIs
Publication statusPublished - Nov 14 2014

Keywords

  • Amyloidogenesis
  • gCJD
  • PrP allotypes
  • PrP
  • Quantitative MS
  • TSE

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Cell Biology
  • Molecular Biology
  • Medicine(all)

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