A genetic variant of PrP, the protein that forms prions, confers protection against the human prion disease kuru by inhibiting the conversion of functional isoforms to the abnormal, disease-causing conformation. See Letter p.478
The group of neurodegenerative disorders known as transmissible spongiform encephalopathies are incurable and lethal. They are caused by prions, a type of infectious agent that has challenged our understanding of the concepts of infection and inheritance. In prion diseases, an abnormal isoform of prion protein (PrP), dubbed PrPSc, induces conformational change in the functional isoform PrPC. The functional form adopts a disease-causing structure, and these abnormal proteins propagate throughout the brain, damaging nerves. But the mechanistic underpinnings of this infectious propagation remain enigmatic. On page 478 of this issue, Asante et al.1 describe a form of PrPC that seems to be resistant to such conformational change, providing some insight into the long-standing issue of whether it is possible to prevent prion diseases.
Kuru, a human prion disease, became a leading cause of death among the Fore population of the highlands of Papua New Guinea in the mid-twentieth century2, killing more than 3,000 people in a population of 30,000. The aetiology of the disease was initially puzzling, but in 1966, a study3 showed that brain extracts from people who had kuru caused progressive neurodegeneration when introduced into chimpanzees, following a prolonged incubation period. This supported the idea that kuru is an infectious disorder. In fact, kuru is a devastating consequence of ritualistic cannibalism, in which the brains and other body parts of tribal members were consumed as an act of mourning.
Fast forward to the end of the twentieth century, and interest in the kuru epidemic was renewed in response to the emergence of variant Creutzfeldt–Jakob disease (vCJD). This human prion disease results from exposure to prions that cause bovine spongiform encephalopathy, carried by cows with 'mad cow' disease. Then, in 2009, the authors of the current study discovered a genetic variant (a polymorphism) in PRNP, the gene that encodes PrP (ref. 4). The variant, which changes the amino acid at residue 127 from glycine (G) to valine (V), was present in one of the two copies of PRNP (mammals have two copies of each chromosome) in unaffected individuals in the kuru-exposed population. The authors proposed that the variant, called V127, conferred resistance to prion disease, and that it had been selected for in response to the kuru epidemic.
Asante et al. set out to compare V127 with another polymorphism in close proximity — amino-acid residue 129 of PrP, which can be either methionine (M) or V. It is thought that one copy of each 129 variant confers some resistance to human prion diseases by affecting the binding between identical prion proteins that is required for conformational change. The researchers injected human prions into mice engineered to express human forms of PrP harbouring different combinations of the two genetic variants.
Mice with one copy of V127 were completely protected against kuru prions, and died of old age without developing neurological disease. By contrast, all mice without V127 developed disease after around 200 days, regardless of the variant at residue 129, confirming that this model system accurately recapitulates the resistance to kuru conferred by V127. Previous work5 has indicated that the transmission properties of kuru are similar to those of the sporadic form of CJD (sCJD), and so it probably came as no surprise to the authors to find that mice with one copy of V127 were also protected from sCJD prions. Interestingly, however, not all of these mice were protected against vCJD prions.
Remarkably, mice carrying two copies of V127 were completely protected against all forms of human prion disease (Fig. 1), indicating that the polymorphism at residue 127 acts in a different manner from that at 129. These mice failed to manifest any signs of prion disease, a noteworthy response that was mimicked only in mice that did not express any prion protein. Finally, Asante et al. investigated how the protective effect of one copy of V127 varied when wild-type PrP (in which the genetic sequence includes the G127 and M129 variants) was expressed at different levels. These experiments demonstrated that V127 acts as a 'dominant negative' inhibitor of prion conversion — not only is it itself resistant to conformational conversion, but it also inhibits conversion of wild-type proteins.
It will be important to learn what structural consequences, if any, occur when V replaces G at residue 127. There are currently no treatments or cures for transmissible spongiform encephalopathies, and structural information may hint at ways to inhibit PrPSc propagation and maintain normal PrPC function. Approaches that capitalize on the profound dominant-negative properties of V127 are obvious targets for further investigation.
V127 was naturally selected in response to epidemic human prion disease. In a similar manner to DNA- or RNA-based infectious agents, prions are subject to Darwinian forces, such that the structure of the disease-causing protein can be altered through selective pressure6. This begs the question of whether new prion strains might emerge to counter the protective effects of the V127 variant. It will be interesting to determine whether V127 also prevents conformational changes in PrP in experimental models of prion amplification, which have been shown to enable interspecies prion transmission7, and if so, what the infectious properties of the resulting prions might be. Finally, it will be valuable to investigate the V127 polymorphism in the context of PrP from other species that are naturally susceptible to prion diseases, using similar approaches to those in the current study. This should help to ascertain whether the effects of this fascinating variant are universally protective against all combinations of species and prion strains.