Prion transmission

Gough, Kevin C.; Maddison, Ben C.

doi:10.4161/pri.4.4.13678

Cited by 124 publications

(60 citation statements)

References 102 publications

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“…Whatever the case, ubiquitous expression of PrP in Drosophila may provide an environment for enhanced uptake and neuroinvasion of scrapie-infected material and generation of the toxic agent compared to panneuronal expression, which may be more important for the response to atypical scrapie prion inocula. In mammalian species, PrPC is ubiquitously expressed, a feature that plays an essential role in the transmission of prion infectivity in naturally acquired cases of prion disease (58), which may include atypical scrapie (41,42). However, not all of the ovine PrP transgenic fly lines used here required ubiquitous expression of PrP in order to succumb to atypical scrapie prion inocula.…”

Section: Discussionmentioning

confidence: 99%

Cytosolic PrP Can Participate in Prion-Mediated Toxicity

Thackray

Zhang

Arndt

et al. 2014

J Virol

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Prion diseases are characterized by a conformational change in the normal host protein PrPC. While the majority of mature PrPC is tethered to the plasma membrane by a glycosylphosphatidylinositol anchor, topological variants of this protein can arise during its biosynthesis. Here we have generated Drosophila transgenic for cytosolic ovine PrP in order to investigate its toxic potential in flies in the absence or presence of exogenous ovine prions. While cytosolic ovine PrP expressed in Drosophila was predominantly detergent insoluble and showed resistance to low concentrations of proteinase K, it was not overtly detrimental to the flies. However, Drosophila transgenic for cytosolic PrP expression exposed to classical or atypical scrapie prion inocula showed a faster decrease in locomotor activity than similar flies exposed to scrapie-free material. The susceptibility to classical scrapie inocula could be assessed in Drosophila transgenic for panneuronal expression of cytosolic PrP, whereas susceptibility to atypical scrapie required ubiquitous PrP expression. Significantly, the toxic phenotype induced by ovine scrapie in cytosolic PrP transgenic Drosophila was transmissible to recipient PrP transgenic flies. These data show that while cytosolic PrP expression does not adversely affect Drosophila, this topological PrP variant can participate in the generation of transmissible scrapie-induced toxicity. These observations also show that PrP transgenic Drosophila are susceptible to classical and atypical scrapie prion strains and highlight the utility of this invertebrate host as a model of mammalian prion disease. IMPORTANCEDuring prion diseases, the host protein PrPC converts into an abnormal conformer, PrPSc, a process coupled to the generation of transmissible prions and neurotoxicity. While PrPC is principally a glycosylphosphatidylinositol-anchored membrane protein, the role of topological variants, such as cytosolic PrP, in prion-mediated toxicity and prion formation is undefined. Here we generated Drosophila transgenic for cytosolic PrP expression in order to investigate its toxic potential in the absence or presence of exogenous prions. Cytosolic ovine PrP expressed in Drosophila was not overtly detrimental to the flies. However, cytosolic PrP transgenic Drosophila exposed to ovine scrapie showed a toxic phenotype absent from similar flies exposed to scrapie-free material. Significantly, the scrapie-induced toxic phenotype in cytosolic transgenic Drosophila was transmissible to recipient PrP transgenic flies. These data show that cytosolic PrP can participate in the generation of transmissible prion-induced toxicity and highlight the utility of Drosophila as a model of mammalian prion disease.

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Section: Discussionmentioning

confidence: 99%

Cytosolic PrP Can Participate in Prion-Mediated Toxicity

Thackray

Zhang

Arndt

et al. 2014

J Virol

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“…CWD was first detected in cervids in the late 1960s in Colorado [2,3] and has since spread to an increasing number of other US states and Canadian provinces [4,5]. The disease is transmitted horizontally by contact with pathogenic prions shed in bodily fluids [6,7] and vertically from mother to offspring [8,9]. Once shed, prions have been shown to persist in the environment, potentially remaining infectious and furthering disease spread long after affected deer have dispersed [10–12].…”

Section: Introductionmentioning

confidence: 99%

Influence of the geographic distribution of prion protein gene sequence variation on patterns of chronic wasting disease spread in white-tailed deer (Odocoileus virginianus)

Brandt

Green

Ishida

et al. 2018

Prion

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Managing and controlling the spread of diseases in wild animal populations is challenging, especially for social and mobile species. Effective management benefits from information about disease susceptibility, allowing limited resources to be focused on areas or populations with a higher risk of infection. Chronic wasting disease (CWD), a transmissible spongiform encephalopathy that affects cervids, was detected in Colorado in the late 1960s. CWD was detected in Illinois and Wisconsin in 2002 and has since spread through many counties. Specific nucleotide variations in the prion protein gene (PRNP) sequence have been associated with reduced susceptibility to CWD in white-tailed deer. Though genetic resistance is incomplete, the frequency of deer possessing these mutations in a population is an important factor in disease spread (i.e. herd immunity). In this study we sequenced 625 bp of the PRNP gene from a sampling of 2433 deer from Illinois and Wisconsin. In north-central Illinois where CWD was first detected, counties had a low frequency of protective haplotypes (frequency <0.20); whereas in northwestern Illinois counties, where CWD cases have only more recently been detected, the frequency of protective haplotypes (frequency >0.30) was much higher (p < 0.05). Protective haplotype frequencies varied significantly among infected and uninfected geographic areas. The frequency of protective PRNP haplotypes may contribute to population level susceptibility and may shape the way CWD has spread through Illinois. Analysis of PRNP haplotype distribution could be a useful tool to assess CWD risk and allocate resources to contain and reduce the spread of infection.

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“…Affected animals, apart from suffering from this fatal disorder, pose the risk of transmitting the disease within a flock/herd, either though milk (transmission from scrapieaffected mothers to offsprings 31,32 or via infectious agent dissemination in the environment through affected animals' placenta sheds 33 and/ or excretions). 34 Moreover, binding of the scrapie agent to the soil and preservation of its infectivity for a long time, 35 constitutes a further source of disease dissemination to animals (sheep and goats) sharing the same pasture.…”

Section: Discussionmentioning

confidence: 99%