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ARS Home » Midwest Area » Ames, Iowa » National Animal Disease Center » Virus and Prion Research » Research » Publications at this Location » Publication #392947

Research Project: Elucidating the Pathobiology and Transmission of Transmissible Spongiform Encephalopathies

Location: Virus and Prion Research

Title: Generation of human chronic wasting disease in transgenic mice

item WANG, ZERUI - Case Western Reserve University (CWRU)
item QIN, KEFENG - University Of Chicago
item CAMACHO, MANUEL - Case Western Reserve University (CWRU)
item CALI, IGNAZIO - Case Western Reserve University (CWRU)
item YUAN, JUE - Case Western Reserve University (CWRU)
item SHEN, PINGPING - Case Western Reserve University (CWRU)
item Greenlee, Justin
item KONG, QINGZHONG - Case Western Reserve University (CWRU)
item MASTRIANNI, JAMES - University Of Chicago
item ZOU, WEN-QUAN - Case Western Reserve University (CWRU)

Submitted to: Meeting Proceedings
Publication Type: Proceedings
Publication Acceptance Date: 5/5/2022
Publication Date: 5/20/2022
Citation: Wang, Z., Qin, K., Camacho, M.V., Cali, I., Yuan, J., Shen, P., Greenlee, J.J., Kong, Q., Mastrianni, J.A., Zou, W. 2022. Generation of human chronic wasting disease in transgenic mice. Proceedings of 10th Iberian Congress on Prions, May 19-20, 2022, Vila Real, Portugal.

Interpretive Summary:

Technical Abstract: Chronic wasting disease (CWD) is a cervid prion disease associated with the accumulation of an infectious misfolded conformer (PrPSc) of cellular prion protein (PrPC) in the brain. It has been spreading rapidly in North America and also found in Asia and Europe. Bovine spongiform encephalopathy is the only animal prion disease known to be zoonotic while the transmissibility of CWD to humans remains uncertain. Here we report the generation of the first CWD-derived infectious human PrPSc by elk CWD PrPSc-seeded conversion of PrPC in normal human brain homogenates using in vitro protein misfolding cyclic amplification (PMCA). Western blotting with human PrP selective antibody confirmed that the PMCA-generated protease-resistant PrPSc was derived from the human PrPC substrate. Two lines of humanized transgenic mice expressing human PrP with either Val or Met at the polymorphic codon 129 developed clinical prion disease following intracerebral inoculation with the PMCA-generated CWD-derived human PrPSc. Diseased mice exhibited distinct PrPSc patterns and neuropathological changes in the brain. Our study, using PMCA and animal bioassays, provides the first evidence that CWD PrPSc can cross the species barrier to convert human PrPC into infectious PrPSc that can produce bona fide prion disease when inoculated into humanized transgenic mice. Supported in part by CJD Foundation, NIH, CDC, Michael J. Fox Foundation for Parkinson’s Research, Alzheimer’s Association, and Western Brain Institute.