A naturally occurring variant of the human prion protein completely prevents prion disease

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 state(2). We have now investigated the protective role of this variant and its interaction with the common worldwide M129V PrP polymorphism; V(127) was seen exclusively on a M(129) PRNP allele. Here we demonstrate that transgenic mice expressing both variant and wild type human PrP are completely resistant to both kuru and classical CJD prions (which are closely similar) but can be infected with variant CJD prions, a human prion strain resulting from exposure to BSE prions to which the Fore were not exposed. Remarkably however, mice expressing only PrP V(127) 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 V(127) completely refractory to prion conversion, but acts as a potent dose-dependent inhibitor of wild type prion propagation.