Familial human prion diseases associated with prion protein mutations Y226X and G131V are transmissible to transgenic mice expressing human prion protein

Race, Brent; Williams, Katie; Hughson, Andrew G.; Jansen, Casper; Parchi, Piero; Rozemüller, Annemieke; Chesebro, Bruce

doi:10.1186/s40478-018-0516-2

Cited by 20 publications

(19 citation statements)

References 50 publications

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“…In detail, half of the animals injected with Y226X brain homogenate had PrP Sc detectable in the brain by immunostaining, immunoblot, and PrP amyloid seeding activity assayed by RT‐QuIC, while G131V‐injected mice showed PrP Sc deposition in the brain, although none were positive by immunoblot or RT‐QuIC assay. In contrast, none of the mice injected with Q227X brain had PrP Sc or PrP‐amyloid seeding activity detectable by these methods . Notably, Y226X is the only known truncating PRNP mutation associated with a familial disease that has been shown to be transmissible.…”

Section: Prion Strain Isolation and Characterization: Transmission Stmentioning

confidence: 95%

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

et al. 2019

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Prion diseases are progressive neurodegenerative disorders affecting humans and other mammalian species. The term prion, originally put forward to propose the concept that a protein could be infectious, refers to PrP Sc , a misfolded isoform of the cellular prion protein (PrP C ) that represents the pathogenetic hallmark of these disorders. The discovery that other proteins characterized by misfolding and seeded aggregation can spread from cell to cell, similarly to PrP Sc , has increased interest in prion diseases. Among neurodegenerative disorders, however, prion diseases distinguish themselves for the broader phenotypic spectrum, the fastest disease progression and the existence of infectious forms that can be transmitted through the exposure to diseased tissues via ingestion, injection or transplantation. The main clinicopathological phenotypes of human prion disease include Creutzfeldt-Jakob disease, by far the most common, fatal insomnia, variably protease-sensitive prionopathy, and Gerstmann-Sträussler-Scheinker disease. However, clinicopathological manifestations extend even beyond those predicted by this classification. Because of their transmissibility, the phenotypic diversity of prion diseases can also be propagated into syngenic hosts as prion strains with distinct characteristics, such as incubation period, pattern of PrP Sc distribution and regional severity of histopathological changes in the brain. Increasing evidence indicates that different PrP Sc conformers, forming distinct ordered aggregates, encipher the phenotypic variants related to prion strains. In this review, we summarize the most recent advances concerning the histo-molecular pathology of human prion disease focusing on the phenotypic spectrum of the disease including co-pathologies, the characterization of prion strains by experimental transmission and their correlation with the physicochemical properties of PrP Sc aggregates.

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Section: Prion Strain Isolation and Characterization: Transmission Stmentioning

confidence: 95%

“…In a recent study, brain homogenates from patients carrying the PRNP mutations G131V, Y226X and Q227X were injected intra‐cerebrally into transgenic mice overexpressing human PrP . Transmissions were successful with the former two patients but not with the one carrying Q227X.…”

Section: Prion Strain Isolation and Characterization: Transmission Stmentioning

confidence: 99%

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

et al. 2019

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“…It was discovered later that BSE is able to cross the species barrier and infect humans after oral exposure (Johnson, ). Changes in prion composition and virulence occur during passages through different species (Raymond et al ., ; Race et al ., ), suggesting that the crossing of the species barrier in humans may not emerge directly from the most frequent reservoir (i.e. white‐tailed deer), as occurred with BSE (Bunk, ).…”

Section: Chronic Wasting Disease Biology Epidemiology and Transmissionmentioning

confidence: 99%

“…Notably, CWD was shown to transmit to various species of non-human primates (Marsh et al, 2005). Of particular note, recent studies report transmission of CWD to macaques (Macaca fascicularis) even by oral administration of brain and muscle tissues (Czub et al, 2017) but these results have been questioned (Race et al, 2018). The USA Centers for Disease Control and Prevention (CDC) recommend that people who harvest deer from CWD-affected areas test their deer or elk for CWD and do not consume venison from a known CWD-positive cervid (CDC, 2018a).…”

Section: Chronic Wasting Disease Biology Epidemiology and Tranmentioning

confidence: 99%

The ecology of chronic wasting disease in wildlife

et al. 2019

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Prions are misfolded infectious proteins responsible for a group of fatal neurodegenerative diseases termed transmissible spongiform encephalopathy or prion diseases. Chronic Wasting Disease (CWD) is the prion disease with the highest spillover potential, affecting at least seven Cervidae (deer) species. The zoonotic potential of CWD is inconclusive and cannot be ruled out. A risk of infection for other domestic and wildlife species is also plausible. Here, we review the current status of the knowledge with respect to CWD ecology in wildlife. Our current understanding of the geographic distribution of CWD lacks spatial and temporal detail, does not consider the biogeography of infectious diseases, and is largely biased by sampling based on hunters' cooperation and funding available for each region. Limitations of the methods used for data collection suggest that the extent and prevalence of CWD in wildlife is underestimated. If the zoonotic potential of CWD is confirmed in the short term, as suggested by recent results obtained in experimental animal models, there will be limited accurate epidemiological data to inform public health. Research gaps in CWD prion ecology include the need to identify specific biological characteristics of potential CWD reservoir species that better explain susceptibility to spillover, landscape and climate configurations that are suitable for CWD transmission, and the magnitude of sampling bias in our current understanding of CWD distribution and risk. Addressing these research gaps will help anticipate novel areas and species where CWD spillover is expected, which will inform control strategies. From an ecological perspective, control strategies could include assessing restoration of natural predators of CWD reservoirs, ultrasensitive CWD detection in biotic and abiotic reservoirs, and deer density and landscape modification to reduce CWD spread and prevalence.

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“…In our current studies we inoculated CWD intracerebrally into two different transgenic mice that overexpress human prion protein (M129) at 8–16-fold (tg66) and two to fourfold (tgRM) normal physiologic levels. Tg66 mice express extremely high levels of human prion protein and have been shown to be a very sensitive model for prion transmission [25, 26]. Following extended observation periods, brains from CWD-inoculated mice were tested for prion disease using the highly sensitive RT-QuIC assay, IHC and immunoblot.…”

Section: Introductionmentioning

confidence: 99%

Transmission studies of chronic wasting disease to transgenic mice overexpressing human prion protein using the RT-QuIC assay

Race

Williams

Chesebro

2019

Vet Res

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Chronic wasting disease (CWD) is a fatal prion disease which infects deer, elk and moose. CWD was first described as a wasting syndrome in captive deer in Colorado and Wyoming wildlife facilities from 1967 to 1979. Currently, CWD has been reported in 26 states of the USA, three Canadian provinces, South Korea, Norway and Finland. Since human consumption of cervids is common, it is critical to determine if CWD can infect humans. Published research, including epidemiologic studies and transmission studies using animal models, including transgenic mice that express human prion protein, have suggested existence of a strong species barrier between cervid CWD and humans. In the current study, we tested CWD transmission into two additional strains of transgenic mice (tg66 and tgRM). These mice over-express human prion protein at high levels and are highly sensitive to infection by human-tropic prions. One hundred and eight mice were inoculated intracerebrally with three different sources of CWD. After long periods of observation, brain tissues from CWD-inoculated mice were screened for evidence of prion infection by RT-QuIC, immunohistochemistry (IHC) and immunoblot. No IHC or immunoblot evidence was found to suggest transmission had occurred, and most mice were negative by RT-QuIC assay. However, four mice with inconsistent positive RT-QuIC reactions were detected. The seeding activity detected in these mice may represent a low level of CWD agent, suggesting a possible transfer of CWD infection. Alternatively, these results might be due to false positive reactions or residual CWD inoculum.Electronic supplementary materialThe online version of this article (10.1186/s13567-019-0626-2) contains supplementary material, which is available to authorized users.

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Familial human prion diseases associated with prion protein mutations Y226X and G131V are transmissible to transgenic mice expressing human prion protein

Cited by 20 publications

References 50 publications

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

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

The ecology of chronic wasting disease in wildlife

Transmission studies of chronic wasting disease to transgenic mice overexpressing human prion protein using the RT-QuIC assay

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