Variant CJD

Diack, Abigail B.; Head, Mark W.; McCutcheon, Sandra; Boyle, Aileen; Knight, Richard; Ironside, James W.; Manson, Jean; Will, Robert

doi:10.4161/pri.29237

Cited by 90 publications

(43 citation statements)

References 111 publications

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“…Our approach, focusing on PK-treated PrP Sc , did not allow us to address in depth the issue of the influence of this putative "fully PK-sensitive PrP Sc " on thermostability profile; nevertheless, the lack of an obvious correlation between sedimentation profile (as determined in reference 27) and thermostability (present work) of PK-treated PrP Sc suggests that factors other than size also contribute to the thermostability of PrP Sc aggregates in CJD. The present results, when combined with the growing knowledge on human prion strains, provide novel insights into the relationships between the physicochemical properties of PrP Sc aggregates and disease characteristics such as incidence, phenotypic expression, and transmission properties (5,7,8,10,11,(48)(49)(50). In particular, PrP Sc thermostability appears to largely, although not entirely, correlate with prion replication efficiency expressed either by the attack rate and incubation time after experimental transmission in the most compatible host genotype or by the relative incidence and duration of clinical disease (Table 2).…”

Section: Given That Prpmentioning

confidence: 76%

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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Section: Given That Prpmentioning

confidence: 76%

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 duration varies depending on the type of the disease, but distinction among them is not always clear. [43][44][45][46][47] Archived appendix tissues from UK surveys approximate the prevalence of asymptomatic vCJD infection of 1 in 2,000 persons born during 1941 to 1985. 48 Gill and colleagues suggested that depending on the genetic genotypes some people may harbor the pathologic prion and never develop clinical signs.…”

Section: Bse Surveillance and Epidemiological Trends In Uk And Other mentioning

confidence: 99%

The Risk of Prion Infection through Bovine Grafting Materials

Kim¹,

Rodriguez

Nowzari

2016

Clin Implant Dent Rel Res

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“…There is compelling evidence that BSE is the zoonotic cause of vCJD (Will et al , 1996; Bruce et al , 1997; Hill et al , 1997; Scott et al , 1999; Diack et al , 2014). Exposure to BSE-contaminated UK beef products between 1980, when epidemic transmission of BSE is estimated to have begun in the UK, and 1996 when reinforced regulation of animal feed was implemented there, is considered the major global risk factor for vCJD (Smith and Bradley, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…These uncertainties, as well as the prolonged incubation period of vCJD and strong evidence of its transmissibility by blood transfusion, support ongoing precaution. Current measures to monitor and control BSE and CJD internationally remain key elements of a prudent long-term public health strateg (Diack et al , 2014). …”

Section: Discussionmentioning

confidence: 99%

“…Variant Creutzfeldt-Jakob disease (vCJD) is a human prion disease linked to a prion disease of cattle, bovine spongiform encephalopathy (BSE), which was identified in the UK during the 1980s and subsequently spread internationally (Will et al , 1996; Diack et al , 2014). Between 1994 and 2016, 231 cases of vCJD have been identified in residents of 12 countries [The National CJD Research and Surveillance Unit (NCJDRSU), 2016].…”

Section: Introductionmentioning

confidence: 99%

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A case cluster of variant Creutzfeldt-Jakob disease linked to the Kingdom of Saudi Arabia

Coulthart

Geschwind

Qureshi

et al. 2016

Brain

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As of mid-2016, 231 cases of variant Creutzfeldt-Jakob disease—the human form of a prion disease of cattle, bovine spongiform encephalopathy—have been reported from 12 countries. With few exceptions, the affected individuals had histories of extended residence in the UK or other Western European countries during the period (1980–96) of maximum global risk for human exposure to bovine spongiform encephalopathy. However, the possibility remains that other geographic foci of human infection exist, identification of which may help to foreshadow the future of the epidemic. We report results of a quantitative analysis of country-specific relative risks of infection for three individuals diagnosed with variant Creutzfeldt-Jakob disease in the USA and Canada. All were born and raised in Saudi Arabia, but had histories of residence and travel in other countries. To calculate country-specific relative probabilities of infection, we aligned each patient’s life history with published estimates of probability distributions of incubation period and age at infection parameters from a UK cohort of 171 variant Creutzfeldt-Jakob disease cases. The distributions were then partitioned into probability density fractions according to time intervals of the patient’s residence and travel history, and the density fractions were combined by country. This calculation was performed for incubation period alone, age at infection alone, and jointly for incubation and age at infection. Country-specific fractions were normalized either to the total density between the individual’s dates of birth and symptom onset (‘lifetime’), or to that between 1980 and 1996, for a total of six combinations of parameter and interval. The country-specific relative probability of infection for Saudi Arabia clearly ranked highest under each of the six combinations of parameter × interval for Patients 1 and 2, with values ranging from 0.572 to 0.998, respectively, for Patient 2 (age at infection × lifetime) and Patient 1 (joint incubation and age at infection × 1980–96). For Patient 3, relative probabilities for Saudi Arabia were not as distinct from those for other countries using the lifetime interval: 0.394, 0.360 and 0.378, respectively, for incubation period, age at infection and jointly for incubation and age at infection. However, for this patient Saudi Arabia clearly ranked highest within the 1980–96 period: 0.859, 0.871 and 0.865, respectively, for incubation period, age at infection and jointly for incubation and age at infection. These findings support the hypothesis that human infection with bovine spongiform encephalopathy occurred in Saudi Arabia.

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Variant CJD

Abstract: These authors contributed equally to this work.

Cited by 90 publications

References 111 publications

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

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

The Risk of Prion Infection through Bovine Grafting Materials

A case cluster of variant Creutzfeldt-Jakob disease linked to the Kingdom of Saudi Arabia

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