Mammalian prions, transmissible agents causing lethal neurodegenerative diseases, are composed of assemblies of misfolded cellular prion protein (PrP)1. A novel PrP variant, G127V, was under positive evolutionary selection during the epidemic of kuru—an acquired prion disease epidemic of the Fore population in Papua New Guinea—and appeared to provide strong protection against disease in the heterozygous state2. Here we have investigated the protective role of this variant and its interaction with the common, worldwide M129V PrP polymorphism. V127 was seen exclusively on a M129 PRNP allele. We demonstrate that transgenic mice expressing both variant and wild-type human PrP are completely resistant to both kuru and classical Creutzfeldt–Jakob disease (CJD) prions (which are closely similar) but can be infected with variant CJD prions, a human prion strain resulting from exposure to bovine spongiform encephalopathy prions to which the Fore were not exposed. Notably, mice expressing only PrP V127 were completely resistant to all prion strains, demonstrating a different molecular mechanism to M129V, which provides its relative protection against classical CJD and kuru in the heterozygous state. Indeed, this single amino acid substitution (G→V) at a residue invariant in vertebrate evolution is as protective as deletion of the protein. Further study in transgenic mice expressing different ratios of variant and wild-type PrP indicates that not only is PrP V127 completely refractory to prion conversion but acts as a potent dose-dependent inhibitor of wild-type prion propagation.
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This work was funded by the UK Medical Research Council. We thank all staff at our Biological Services Facility for animal care; C. O’Malley and S. Lyall for technical support with histology; and R. Newton and R. Young for preparation of figures. We thank patients and families for consent to use human tissues. We thank UK neurological and neuropathology colleagues for providing brain tissue from CJD patients. Some of this work was undertaken at University College London Hospitals/University College London, which received a proportion of funding from the Department of Health's National Institute for Health Research Biomedical Research Centres funding scheme. We thank the Fore communities and P. Siba and colleagues at the Papua New Guinea Institute of Medical Research for their long-term support. We thank the late C. Gajdusek, the late J. Gibbs, S. Landis, and their associates from the Laboratory of Central Nervous System Studies of the National Institutes of Health, Bethesda, USA, for archiving and sharing kuru samples.