Refined transgenic mouse models which recapitulate the natural features of chronic wasting disease with rapid prion disease onsets

Authors: DEFRANCO, JOSEPH - Colorado State University; KIM, SEHUN - Colorado State University; ATKINSON, ZOE - Colorado State University; CROWELL, JENNA - Colorado State University; Lei, Samantha; Bian, Jifeng; TELLING, GLENN - Colorado State University

Submitted to: Journal of Infectious Diseases
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/8/2025
Publication Date: 10/16/2025
Citation: DeFranco, J.P., Kim, S., Atkinson, Z.N., Crowell, J., Lei, S.S., Bian, J., Telling, G.C. 2025. Refined transgenic mouse models which recapitulate the natural features of chronic wasting disease with rapid prion disease onsets. Journal of Infectious Diseases. https://doi.org/10.1093/infdis/jiaf529.
DOI: https://doi.org/10.1093/infdis/jiaf529

Interpretive Summary: Prion diseases are a group of fatal and transmissible brain disorders that affect animals and humans. Since 1930s, researchers have used various animal models to study how these diseases spread. A breakthrough came with the discovery of the prion protein gene in 1986, which led to the development of prion gene knockout, transgenic (unregulated gene overexpression model), and gene-targeted (physiological gene expression model) mouse models. Both transgenic and gene-targeted mice have been essential tools in prion research since then, while each model has its strengths and limitations. In this study, we crossbred mice expressing cervid prion proteins and challenged them with chronic wasting disease prions. The resulting hybrid mice not only kept high susceptibility to chronic wasting disease but also showed accelerated disease onset compared to the parental lines. These findings suggest that combining the transgenic overexpressors with gene-target mice can optimize prion disease modeling and may provide a more efficient platform for studying prion diseases. The resources we develop in this work allow laboratory studies using an appropriate animal model to determine prion disease progression, transmission routes, and they will support empirically informed control strategies to minimize the impact of chronic wasting diseases on wildlife and U.S. agriculture.

Technical Abstract: Prion diseases are a group of fatal, neurodegenerative diseases of animals and humans. While conventional transgenic (Tg) mice have successfully overcome the species barrier for natural prion strains, their inherent limitations have led to developing novel gene-targeted (Gt) mice. Although Gt mice offer a more authentic model of prion disease, their experimental utility may be constrained by the expression of exogenous prion protein at wild-type levels. Here, we describe a combination of the Tg and Gt systems, which result in a rapid disease model that accurately recapitulates the native strain properties of chronic wasting disease prions.