Prion Strain Characterization of a Novel Subtype of Creutzfeldt-Jakob Disease

Abstract

In 2007, we reported a patient with an atypical form of CreutzfeldtJakob disease (CJD) heterozygous for methionine-valine (MV) at codon 129 who showed a novel pathological prion protein (PrP TSE ) conformation with an atypical glycoform (AG) profile and intraneuronal PrP deposition. In the present study, we further characterize the conformational properties of this pathological prion protein (PrP TSE MV AG ), showing that PrP TSE MV AG is composed of multiple conformers with biochemical properties distinct from those of PrP TSE type 1 and type 2 of MV sporadic CJD (sCJD). Experimental transmission of CJD-MV AG to bank voles and genetargeted transgenic mice carrying the human prion protein gene (TgHu mice) showed unique transmission rates, survival times, neuropathological changes, PrP TSE deposition patterns, and PrP TSE glycotypes that are distinct from those of sCJD-MV1 and sCJD-MV2. These biochemical and experimental data suggest the presence of a novel prion strain in CJD-MV AG .IMPORTANCE Sporadic Creutzfeldt-Jakob disease is caused by the misfolding of the cellular prion protein, which assumes two different major conformations (type 1 and type 2) and, together with the methionine/valine polymorphic codon 129 of the prion protein gene, contribute to the occurrence of distinct clinical-pathological phenotypes. Inoculation in laboratory rodents of brain tissues from the six possible combinations of pathological prion protein types with codon 129 genotypes results in the identification of 3 or 4 strains of prions. We report on the identification of a novel strain of Creutzfeldt-Jakob disease isolated from a patient who carried an abnormally glycosylated pathological prion protein. This novel strain has unique biochemical characteristics, does not transmit to humanized transgenic mice, and shows exclusive transmission properties in bank voles. The identification of a novel human prion strain improves our understanding of the pathogenesis of the disease and of possible mechanisms of prion transmission.

Recent advances in the histo‐molecular pathology of human prion disease

“…Given that PrP C showed all three glycoforms, the lack of diglycosylated PrP Sc in this case likely represents a strain‐specific property. The results of a transmission study in mice and bank voles supported this interpretation . PrP immunohistochemistry was also distinctive, revealing intraneuronal PrP Sc deposits.…”

“…Over the years, we have encountered a few cases with atypical histopathology associated with a distinctive immunoblot PrP Sc profile characterized by the lack of the diglycosylated band and a type 1‐like migration pattern (P. Parchi personal communication). Recently, the clinicopathological features and transmission properties of a patient with an analog form of PrP Sc have been reported . Given that PrP C showed all three glycoforms, the lack of diglycosylated PrP Sc in this case likely represents a strain‐specific property.…”

Interventions to reduce the risk of surgically transmitted Creutzfeldt–Jakob disease: a cost-effective modelling review

“…The authors note that their findings refute the hypothesis that secondary transmission of a human prion disease results in acquired virulence (or harmfulness). This is supported by a study by Galeno et al, 67 which found that a novel strain from an atypical CJD in a heterogeneous 69-year old woman who had been treated with phospholipids extracted from bovine brains was not transmissible to transgenic mice but transmitted exclusively to bank voles. The authors note that bank voles are susceptible to a variety of human and animal prions with an efficacy that is often higher than that observed in transgenic mice.…”

“…Electronic literature searches were performed to identify articles that report on complication rates associated with the use of single-use versus reusable anaesthetic, diagnostic or surgical instruments. Terms for 'disposable' or single-use' instruments (see Appendix 1, search strategy lines 60-63), including specifically named instruments recommended at the NICE committee meeting in June 2017 (see Appendix 1, search strategy line 63), were combined with 'high-risk surgical procedures' (see Appendix 1, search strategy lines [65][66][67][68][69][70][71][72][73][74][75][76][77][78][79] or 'complications' (see Appendix 1, search strategy lines 81-84). 5.…”

“…The authors note that bank voles are susceptible to a variety of human and animal prions with an efficacy that is often higher than that observed in transgenic mice. 67…”