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

• We elucidated the role of V210I and R208H mutations in the formation of PrPCJD.
• We determined by MS the quantitative ratio of mut/wt PrPCJD allotypes.
• We showed that mutant PrPCJD allotypes exceeds of 2- or 3-fold the amount of the wt.
• Mutant residues may increase the concentration of PrPC and facilitate misfolding.
• Mutant PrP likely accelerates the initial stage of PrPCJD formation.

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.

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