Generation of human chronic wasting disease in transgenic mice

Chronic wasting disease (CWD) is a cervid prion disease caused by the accumulation of an infectious misfolded conformer (PrP(Sc)) of cellular prion protein (PrP(C)). It has been spreading rapidly in North America and also found in Asia and Europe. Although bovine spongiform encephalopathy (i.e. mad cow disease) is the only animal prion disease known to be zoonotic, the transmissibility of CWD to humans remains uncertain. Here we report the generation of the first CWD-derived infectious human PrP(Sc) by elk CWD PrP(Sc)-seeded conversion of PrP(C) 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 PrP(Sc) was derived from the human PrP(C) 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 PrP(Sc). Diseased mice exhibited distinct PrP(Sc) patterns and neuropathological changes in the brain. Our study, using PMCA and animal bioassays, provides the first evidence that CWD PrP(Sc) can cross the species barrier to convert human PrP(C) into infectious PrP(Sc) that can produce bona fide prion disease when inoculated into humanized transgenic mice. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40478-021-01262-y.