Experimental Verification of a Traceback Phenomenon in Prion Infection

Kobayashi, Atsushi; Sakuma, Nobuyuki; Matsuura, Yuichi; Mohri, Satoshi; Aguzzi, Adriano; Kitamoto, Tetsuyuki

doi:10.1128/jvi.02387-09

Cited by 65 publications

(112 citation statements)

References 27 publications

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“…On the basis of the findings from the present study, together with data from previous studies (2,3,5), we propose the neuropathological and biochemical criteria that may help distinguish acquired CJD caused by transmission of the V2 sCJD strain to individuals with the 129M/M genotype, here denoted acquired CJD-MMiK (the 129 M/M genotype, type i PrP Sc , and kuru plaques), from sporadic CJD. Since widespread kuru plaques have also been reported in pituitary hormone-associated iatrogenic CJD cases with the 129M/M genotype (28,29), the type of PrP Sc in these cases needs to be examined in the future.…”

Section: Discussionmentioning

confidence: 93%

“…Type i PrP Sc (20 kDa) was reproduced in the 129M/M mice inoculated with brain homogenates from the atypical CJD cases or plaque-type dCJD. Details of the transmission properties of plaque-type dCJD, sCJD-MM1, or sCJD-VV2 have been reported previously (2,3,5). Plaque-type, plaque-type dCJD.…”

Section: Discussionmentioning

confidence: 99%

“…Phenotypic heterogeneity can also be recognized in transmission experiments using PrP-humanized knock-in mice, depending on both the inoculated CJD strain and the codon 129 genotype of the recipient animals (2)(3)(4). For example, sCJD-MM1 or sCJD-MV1 prions, representing the most common CJD strain (denoted strain M1 [4]), induce the same phenotype, i.e., diffuse synaptic-type PrP deposition and type 1 PrP Sc accumulation resembling those observed in sCJD-MM1 or sCJD-MV1 patients, regardless of the mouse codon 129 genotype.…”

Section: Importancementioning

confidence: 99%

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Transmission Properties of Atypical Creutzfeldt-Jakob Disease: a Clue to Disease Etiology?

Kobayashi

Parchi

Yamada

et al. 2015

J Virol

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The genotype at polymorphic codon 129 of the PRNP gene has a profound influence on both phenotypic expression and prion strain susceptibility in humans. For example, while the most common sporadic Creutzfeldt-Jakob disease (CJD) subtype, sporadic CJD-MM1 (M1 strain), induces a single phenotype after experimental transmission regardless of the codon 129 genotype of the recipient animal, the phenotype elicited by sporadic CJD-VV2 (V2 strain), the second most common subtype, varies according to the host codon 129 genotype. In particular, the propagation of the V2 strain in codon 129 methionine homozygotes has been linked only to acquired forms of CJD such as plaque-type dura mater graft-associated CJD (dCJD), a subgroup of iatrogenic CJD with distinctive phenotypic features, but has never been observed in sporadic CJD cases. In the present report, we describe atypical CJD cases carrying codon 129 methionine homozygosity, in a neurosurgeon and in a patient with a medical history of neurosurgery without dural grafting, showing the distinctive phenotypic features and transmission properties of plaque-type dCJD. These findings raise the possibility that the two cases, previously thought to represent sporadic CJD, might actually represent acquired CJD caused by infection with the V2 strain. Thus, careful analyses of phenotypic features and transmission properties in atypical cases may be useful to distinguish acquired from sporadic cases of CJD. IMPORTANCESusceptibility to and phenotypic expression of Creutzfeldt-Jakob disease (CJD) depend on both the prion strain and genotype at polymorphic codon 129 of the PRNP gene. For example, propagation of the second most common sporadic CJD strain (V2 strain) into codon 129 methionine homozygotes has been linked to plaque-type dura mater graft-associated CJD (dCJD), a subgroup of iatrogenic CJD with distinctive phenotypic features, but has never been observed in sporadic CJD. In the present report, we describe atypical CJD cases in a neurosurgeon and in a patient with a medical history of neurosurgery without dural grafting, showing the distinctive phenotypic features and transmission properties of plaque-type dCJD. These findings raise the possibility that the two cases, previously considered to represent sporadic CJD, might actually represent acquired CJD caused by infection with the V2 strain.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Importancementioning

confidence: 99%

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Transmission Properties of Atypical Creutzfeldt-Jakob Disease: a Clue to Disease Etiology?

Kobayashi

Parchi

Yamada

et al. 2015

J Virol

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“…vCJD represents human infection with BSE from cattle (17). This phenomenon has been designated as "traceback," and traceback studies have been proven to be a useful tool to identify the origin of prions (17,(25)(26)(27). Therefore, we examined whether the transmissibility to Ki-Bov/Bov was maintained among humanized mouse-passaged vCJD prions.…”

Section: Transmission Of Vcjd Prions To Knock-in Mice Expressingmentioning

confidence: 99%

Characterization of Variant Creutzfeldt-Jakob Disease Prions in Prion Protein-humanized Mice Carrying Distinct Codon 129 Genotypes

Takeuchi

Kobayashi

Ironside

et al. 2013

Journal of Biological Chemistry

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Background: Secondary vCJD infection may occur in all human PRNP genotypes, but its clinicopathological and biochemical phenotype is uncertain. Results: The biochemical characteristics and transmission properties of the newly generated vCJD prions are not affected by the host PRNP genotypes. Conclusion: Secondary vCJD infection can be adequately diagnosed by biochemical analysis and experimental transmission. Significance: Effective means to identify secondary vCJD infection are presented.

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“…The current classification of sporadic Creutzfeldt-Jakob disease (sCJD), the most common human prion disease, includes six major disease phenotypes that strongly correlate at the molecular level with the genotype at the polymorphic codon 129 (methionine [M] or valine [V]) of the PRNP gene (which encodes PrP C ) and two PrP Sc profiles or types (type 1 and type 2) comprising distinctive physicochemical properties such as size after protease treatment (respectively, 21 and 19 kDa) and glycoform ratio (4,5). Recent studies in animal models have shown that phenotypic variations among sCJD phenotypes are largely maintained after transmission into genetically defined hosts, suggesting that different prion strains are the main cause of this diversity (6)(7)(8)(9)(10)(11). Although it is well established that PrP C conversion into PrP Sc involves consistent changes in the secondary structure with part of the ␣-helical structure turning into a ␤-sheet (12,13), a complete structural characterization of PrP Sc has been hampered by the propensity of the misfolded protein to form highly aggregated and detergent-insoluble polymers.…”

mentioning

confidence: 99%

Analysis of Conformational Stability of Abnormal Prion Protein Aggregates across the Spectrum of Creutzfeldt-Jakob Disease Prions

Cescatti

Saverioni

Capellari

et al. 2016

J Virol

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The wide phenotypic variability of prion diseases is thought to depend on the interaction of a host genotype with prion strains that have self-perpetuating biological properties enciphered in distinct conformations of the misfolded prion protein PrP Sc . This concept is largely based on indirect approaches studying the effect of proteases or denaturing agents on the physicochemical properties of PrP Sc aggregates. Furthermore, most data come from studies on rodent-adapted prion strains, making current understanding of the molecular basis of strains and phenotypic variability in naturally occurring diseases, especially in humans, more limited. To fill this gap, we studied the effects of guanidine hydrochloride (GdnHCl) and heating on PrP Sc aggregates extracted from 60 sporadic Creutzfeldt-Jakob disease (CJD) and 6 variant CJD brains. While denaturation curves obtained after exposure of PrP Sc to increasing GdnHCl concentrations showed similar profiles among the 7 CJD types analyzed, PrP Sc exposure to increasing temperature revealed significantly different and type-specific responses. In particular, MM1 and VV2, the most prevalent and fast-replicating CJD types, showed stable and highly resistant PrP Sc aggregates, whereas VV1, a rare and slowly propagating type, revealed unstable aggregates that easily dissolved at low temperature. Taken together, our results indicate that the molecular interactions mediating the aggregation state of PrP Sc , possibly enciphering strain diversity, are differently targeted by GdnHCl, temperature, and proteases. Furthermore, the detected positive correlation between the thermostability of PrP Sc aggregates and disease transmission efficiency makes inconsistent the proposed hypothesis that a decrease in conformational stability of prions results in an increase in their replication efficiency. IMPORTANCEPrion strains are defined as infectious isolates propagating distinctive phenotypic traits after transmission to syngeneic hosts. Although the molecular basis of prion strains is not fully understood, it is largely accepted that variations in prion protein conformation drive the molecular changes leading to the different phenotypes. In this study, we exposed abnormal prion protein aggregates encompassing the spectrum of human prion strains to both guanidine hydrochloride and thermal unfolding. Remarkably, while exposure to increasing temperature revealed significant strain-specific differences in the denaturation profile of the protein, treatment with guanidine hydrochloride did not. The findings suggest that thermal and chemical denaturation perturb the structure of prion protein aggregates differently. Moreover, since the most thermostable prion protein types were those associated with the most prevalent phenotypes and most rapidly and efficiently transmitting strains, the results suggest a direct correlation between strain replication efficiency and the thermostability of prion protein aggregates. P rion diseases are invariably fatal neurodegenerative disorders of humans ...

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Experimental Verification of a Traceback Phenomenon in Prion Infection

Cited by 65 publications

References 27 publications

Transmission Properties of Atypical Creutzfeldt-Jakob Disease: a Clue to Disease Etiology?

Transmission Properties of Atypical Creutzfeldt-Jakob Disease: a Clue to Disease Etiology?

Characterization of Variant Creutzfeldt-Jakob Disease Prions in Prion Protein-humanized Mice Carrying Distinct Codon 129 Genotypes

Analysis of Conformational Stability of Abnormal Prion Protein Aggregates across the Spectrum of Creutzfeldt-Jakob Disease Prions

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