Chronic wasting disease (CWD) is a transmissible spongiform encephalopathy that can affect North American cervids (deer, elk, and moose). Using a novel in vitro conversion system based on incubation of prions with normal brain homogenates, we now report that PrPCWD of elk can readily induce the conversion of normal cervid PrP(PrPC) molecules to a protease-resistant form, but is less efficient in converting the PrPC of other species, such as human, bovine, hamster, and mouse. However, when substrate brain homogenates are partially denatured by acidic conditions (pH 3.5), PrPCWD-induced conversion can be greatly enhanced in all species. Our results demonstrate that PrPC from cervids (including moose) can be efficiently converted to a protease-resistant form by incubation with elk CWD prions, presumably due to sequence and structural similarities between these species. Moreover, partial denaturation of substrate PrPC can apparently overcome the structural barriers between more distant species. (C) 2007 Elsevier Inc. All rights reserved.