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). 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. 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.

Biohazards of investigations on the transmissible spongiform encephalopathies.

There is considerable current interest in the agents that cause the spongiform encephalopathies: scrapie, transmissible mink encephalopathy, kuru, and Creutzfeldt-Jakob disease (CJD). The unusual properties of these agents, their elusiveness, and their pathogenicity for humans (in the cases of kuru and CJD) make these agents interesting subjects of investigation but also make imperative a consideration of their potential biohazards in the laboratory. In view of both the potential pathogenicity of these agents and the potential hazards of many laboratory procedures, a series of physical containment levels, each of which corresponds to a range of composite risk factors, are suggested. The estimated composite risk factor used is a function of the potential pathogenicity or relative risk factor of the agent and the potential hazard of a laboratory procedure. The lowest risk factors (1 to 2+) correspond to levels of containment similar to those recommended by the Center for Disease Control for class II microorganisms, while the highest risk factors (5 to 8+) correspond to levels similar to those for class III microorganisms. The use of such a biohazard ranking system aids in a rational approach to selection of equipment and procedures.