Generation of human chronic wasting disease in transgenic mice

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

Submitted to: Acta Neuropathologica
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/8/2021
Publication Date: 9/26/2021
Citation: Wang, Z., Qin, K., Camacho, M., Ignazio, C., Yuan, J., Shen, P., Greenlee, J.J., Kong, Q., Mastrianni, J., Zou, W. 2021. Generation of human chronic wasting disease in transgenic mice. Acta Neuropathologica. 9. Article 158. https://doi.org/10.1186/s40478-021-01262-y.
DOI: https://doi.org/10.1186/s40478-021-01262-y

Interpretive Summary: Prion diseases are invariably fatal neurologic diseases for which there is no known prevention or cure. Chronic wasting disease (CWD) is the prion disease of deer and elk and is present in farmed and free ranging herds throughout North America. To date there is no clear evidence that the CWD agent could be transmitted to humans. This manuscript describes the use of an in vitro technique, cell-free serial protein misfolding cyclic amplification (sPMCA), to generate a CWD prion that is infectious to transgenic mice expressing the human prion protein. This study provides the first evidence that CWD prions may be able to cause misfolding in the human prion protein. This information will impact medical experts and those involved in making policy for farmed cervids and wildlife.

Technical Abstract: Chronic wasting disease (CWD) is a cervid spongiform encephalopathy or prion disease caused by the infectious prion or PrPSc, a misfolded conformer of cellular prion protein (PrPC). It has rapidly spread in North America and also has been found in Asia and Europe. In contrast to the zoonotic mad cow disease that is the first animal prion disease found transmissible to humans, the transmissibility of CWD to humans remains uncertain although most previous studies have suggested that humans may not be susceptible to CWD. Here we report the generation of an infectious human PrPSc by seeding CWD PrPSc in normal human brain PrPC through the in vitro cell-free serial protein misfolding cyclic amplification (sPMCA). Western blotting confirms that the sPMCA-induced proteinase K-resistant PrPSc is a human form, evidenced by a PrP-specific antibody that recognizes human but not cervid PrP. Remarkably, two lines of humanized transgenic (Tg) mice expressing human PrP-129Val/Val (VV) or -129Met/Met (MM) polymorphism develop prion disease at 233 ± 6 (mean ± SE) days post-inoculation (dpi) and 552 ± 27 dpi, respectively, upon intracerebral inoculation with the sPMCA-generated PrPSc. The brain of diseased Tg mice reveals the electrophoretic profile of PrPSc similar to sporadic Creutzfeldt-Jakob disease (sCJD) MM1 or VV2 subtype but different neuropathological patterns. We believe that our study provides the first evidence that CWD PrPSc is able to convert human PrPC into PrPSc in vitro and the CWD-derived human PrPSc mimics atypical sCJD subtypes in humanized Tg mice.