Spontaneous generation of rapidly transmissible prions in transgenic mice expressing wild-type bank vole prion protein

Watts, Joel C.; Giles, Kurt; Stöhr, Jan; Oehler, Abby; Bhardwaj, Sumita; Grillo, Sunny K.; Patel, Smita S.; DeArmond, Stephen J.; Prusiner, Stanley B.

doi:10.1073/pnas.1121556109

Cited by 67 publications

(103 citation statements)

References 47 publications

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“…Even very large vectors such as those created by BACs can have variable spatial expression patterns (35). This likely explains why some lines overexpressing WT PrP become sick (9)(10)(11). It also highlights why, in the rare past cases in which spontaneous infectivity has been generated by extremely high overexpression levels in transgenic mice, it has been difficult to determine how much the mutation contributed to the result (36).…”

Section: Discussionmentioning

confidence: 97%

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Profoundly different prion diseases in knock-in mice carrying single PrP codon substitutions associated with human diseases

Jackson

Borkowski

Watson

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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In man, mutations in different regions of the prion protein (PrP) are associated with infectious neurodegenerative diseases that have remarkably different clinical signs and neuropathological lesions. To explore the roots of this phenomenon, we created a knock-in mouse model carrying the mutation associated with one of these diseases [Creutzfeldt-Jakob disease (CJD)] that was exactly analogous to a previous knock-in model of a different prion disease [fatal familial insomnia (FFI)]. Together with the WT parent, this created an allelic series of three lines, each expressing the same protein with a single amino acid difference, and with all native regulatory elements intact. The previously described FFI mice develop neuronal loss and intense reactive gliosis in the thalamus, as seen in humans with FFI. In contrast, CJD mice had the hallmark features of CJD, spongiosis and proteinase K-resistant PrP aggregates, initially developing in the hippocampus and cerebellum but absent from the thalamus. A molecular transmission barrier protected the mice from any infectious prion agents that might have been present in our mouse facility and allowed us to conclude that the diseases occurred spontaneously. Importantly, both models created agents that caused a transmissible neurodegenerative disease in WT mice. We conclude that single codon differences in a single gene in an otherwise normal genome can cause remarkably different neurodegenerative diseases and are sufficient to create distinct protein-based infectious elements.neurodegeneration | protein aggregation | protein misfolding | transgenic mice

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Section: Discussionmentioning

confidence: 97%

“…Indeed, this may explain why most mouse models that have been engineered this way are disease-free. Moreover, because mice with very high overexpression of WT PrP can develop diseases (9)(10)(11), in transgenic models, it is difficult to distinguish between the effects of the mutation from the effects of overexpression.…”

mentioning

confidence: 99%

Profoundly different prion diseases in knock-in mice carrying single PrP codon substitutions associated with human diseases

Jackson

Borkowski

Watson

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Tg mice expressing the Ile-109 polymorphic variant of bank vole PrP develop a spontaneous neurodegenerative disease that recapitulates all of the neuropathological hallmarks of prion disease (Fig. 1, right column) (64). This disease was rapidly transmissible to Tg mice expressing bank vole PrP, with incubation periods as short as 35 days, and could also be transmitted to Tg mice overexpressing mouse PrP and to WT mice.…”

Section: Spontaneous Generation Of Infectious Prions In Micementioning

confidence: 91%

Mouse Models for Studying the Formation and Propagation of Prions

Watts

Prusiner

2014

Journal of Biological Chemistry

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Prions are self-propagating protein conformers that cause a variety of neurodegenerative disorders in humans and animals. Mouse models have played key roles in deciphering the biology of prions and in assessing candidate therapeutics. The development of transgenic mice that form prions spontaneously in the brain has advanced our understanding of sporadic and genetic prion diseases. Furthermore, the realization that many proteins can become prions has necessitated the development of mouse models for assessing the potential transmissibility of common neurodegenerative diseases. As the universe of prion diseases continues to expand, mouse models will remain crucial for interrogating these devastating illnesses.

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“…Misfolding of PrP is associated with an increase in the ␤-sheet content of the protein, which accumulates principally in the central nervous system of an affected individual. There is now considerable evidence to suggest that the transmissible prion agent comprises PrPSc (8)(9)(10)(11)(12)(13)(14). However, despite intensive investigation, the molecular mechanisms of PrPC-toPrPSc conversion and of prion-mediated neurodegeneration remain unknown.…”

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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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Spontaneous generation of rapidly transmissible prions in transgenic mice expressing wild-type bank vole prion protein

Cited by 67 publications

References 47 publications

Profoundly different prion diseases in knock-in mice carrying single PrP codon substitutions associated with human diseases

Profoundly different prion diseases in knock-in mice carrying single PrP codon substitutions associated with human diseases

Mouse Models for Studying the Formation and Propagation of Prions

Cytosolic PrP Can Participate in Prion-Mediated Toxicity

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