Abstract
Prion diseases are infectious neurodegenerative disorders that affect humans and animals and that result from the conversion of normal prion protein (PrP(C)) into the misfolded prion protein (PrP(Sc)). Chronic wasting disease (CWD) is a prion disorder of increasing prevalence within the United States that affects a large population of wild and captive deer and elk. Determining the risk of transmission of CWD to humans is of utmost importance, considering that people can be infected by animal prions, resulting in new fatal diseases. To study the possibility that human PrP(C) can be converted into the misfolded form by CWD PrP(Sc), we performed experiments using the protein misfolding cyclic amplification technique, which mimics in vitro the process of prion replication. Our results show that cervid PrP(Sc) can induce the conversion of human PrP(C) but only after the CWD prion strain has been stabilized by successive passages in vitro or in vivo. Interestingly, the newly generated human PrP(Sc) exhibits a distinct biochemical pattern that differs from that of any of the currently known forms of human PrP(Sc). Our results also have profound implications for understanding the mechanisms of the prion species barrier and indicate that the transmission barrier is a dynamic process that depends on the strain and moreover the degree of adaptation of the strain. If our findings are corroborated by infectivity assays, they will imply that CWD prions have the potential to infect humans and that this ability progressively increases with CWD spreading.
Highlights
Chronic wasting disease (CWD)2 is a disorder associated with infectious prions that affects deer, elk, and moose [1, 2]
Defining that risk is of utmost importance, considering that transmission of bovine prions to humans resulted in a new disease (variant Creutzfeldt-Jakob disease (CJD)) and that the number of cervids affected by CWD in the United States is increasing [3]
Having validated the protein misfolding cyclic amplification (PMCA) technology to assess the species barrier in vitro [16, 17], we investigated the possibility that CWD PrPSc can convert human PrPC to PrPSc
Summary
Chronic wasting disease (CWD) is a disorder associated with infectious prions that affects deer, elk, and moose [1, 2]. Defining that risk is of utmost importance, considering that transmission of bovine prions to humans resulted in a new disease (variant Creutzfeldt-Jakob disease (CJD)) and that the number of cervids affected by CWD in the United States is increasing [3]. The strength of the barrier between different species is unpredictable and requires bioassay studies to be assessed. These experiments are costly and time-consuming and, in the case of humans, cannot be measured directly but rely on the use of animal models, such as transgenic mice and primates. New prion strains can be generated, adapted, and stabilized upon crossing species barriers in vitro by PMCA [16, 17]. Conversion of Human PrPC by Cervid PrPSc and the expected features of the new infectious material produced
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