By Eleanor McDermid, Senior medwireNews Reporter
A naturally occurring variant of the human prion protein (PrP) is not only resistant to conversion into an abnormal form but also prevents the conversion of wild-type proteins, shows a study in Nature.
The variant, in which a glycine at residue 127 is replaced by a valine (V127), occurred because of evolutionary selection in a population in a remote area of Papua New Guinea, where a prion disease (kuru) acquired through ritual cannibalism formerly killed around 2% of the population each year.
In the current study, the team that uncovered the variant – John Collinge (UCL Institute of Neurology, London, UK) and colleagues – tested its effects in transgenic mice.
They report that mice carrying just one copy of V127 were completely resistant to infection with all four isolates of kuru and four classical Creutzfeldt–Jakob disease (CJD) isolates, instead dying naturally of old age. By contrast, 100% of mice with M127 developed clinical disease. However, about 10% of mice heterozygous for V127 developed disease on exposure to variant (v)CJD and about 70% had subclinical signs of infection.
But mice with two copies of V127 were resistant to all 18 human prion disease isolates, including vCJD; they did not even have evidence of subclinical infection.
Study first author Emmanuel Asante (UCL Institute of Neurology) said in a press release that the team were expecting the mice to show partial resistance. “However, we were surprised that the mice were completely protected from all human prion strains. The result could not have been clearer or more dramatic.”
This differentiates V127 from the nearby, previously established M129V polymorphism, which confers partial resistance only in people heterozygous for the polymorphism. Mice heterozygous for both the M127V and M129V polymorphisms were partially resistant to infection with kuru and classical CJD, but the rate of infection and clinical disease was greater in mouse strains with higher expression of wild-type PrP.
Also, the presence of even one copy of V127 lengthened the time between infection and clinical symptoms, which, altogether, led the researchers to conclude that V127 has a strong dominant-negative effect. In other words, it is not only itself resistant to prion disease but confers resistance upon wild-type PrP present within the cell.
In a commentary accompanying the study, Glenn Telling (Colorado State University, Fort Collins, USA) says: “It will be important to learn what structural consequences, if any, occur when V replaces G at residue 127.”
He notes the current lack of treatments for prion diseases and suggests that structural study of prion proteins may yield clues to treatment. “Approaches that capitalize on the profound dominant-negative properties of V127 are obvious targets for further investigation.”
medwireNews is an independent medical news service provided by Springer Healthcare Limited. © Springer Healthcare Ltd; 2015
Licensed from medwireNews with permission from Springer Healthcare Ltd. ©Springer Healthcare Ltd. All rights reserved. Neither of these parties endorse or recommend any commercial products, services, or equipment.