Scientists show that prions “lifeless” are capable of evolutionary change and adaptation

The research may point to more effective therapeutic targets for deadly diseases by prions

Scientists at the Scripps Research Institute have determined for the first time that prions, infectious protein fragments devoid of DNA or RNA that can cause fatal neurodegenerative diseases, are capable of Darwinian evolution.

The study of Scripps Florida in Jupiter, USA, shows that prions may develop a large number of mutations at the level of protein and, through natural selection, these mutations can produce evolutionary adaptations such as resistance to drugs, a phenomenon that was known before only in bacteria and viruses. These findings also indicate that the normal prion protein, which occurs naturally in human cells, can become a focus of treatment more effective than their abnormal toxic relationship.

The study was published on 31 December 2009 in the journal Science Express, an advance online edition of the prestigious journal Science.

“In view of this, it has exactly the same process of change and adaptive change in the prion that is seen in viruses,” said Charles Weissmann, MD, Ph.D., director of the Scripps Florida Department of Infectious Diseases, who led the study. “This means that this pattern of Darwinian evolution seems to be universally active. In viruses, the mutation is associated with changes in nucleic acid sequence that leads to resistance. Now this adaptation is moved one level down-to prions and protein folding, and it is clear that no nucleic acid is required for the process of evolution. ”

Prions (short for proteinaceous infectious particles) are associated with infectious about 20 different diseases in humans and animals, including mad cow disease and a rare human form, the Creutzfeldt-Jakob disease. All these diseases are untreatable and eventually fatal. Prions, which are composed solely of protein, are classified into different strains, originally characterized by incubation time and disease they cause. Prions have the ability to reproduce, although not containing a nucleic acid genome.

Mammalian cells normally produce or cellular prion protein PrPC. During infection, an abnormal or misfolded protein, known as PrPSc-converts normal prion protein in its toxic form host, changing its conformation or shape. The final phase consists of large ensembles (polymers) of these misfolded proteins, causing massive damage to tissues and cells.

“It was generally thought that once the cellular prion protein is converted into the abnormal form, there was no further change,” said Weissmann. “But there were signs that something was happening. By transmitting prions from sheep to mice, they become more virulent over time. We now know that abnormal prions replicate and create variants, perhaps at a low level at first. But once they are transferred to a new host, eventually natural selection chooses the most virulent and aggressive variants.

Drug resistance

In the first part of the study, Weissman and colleagues transferred prion populations of brain cells infected cultured cells. When transplanted, the cells adapted prions were developed and competed with their counterparts adapted to the brain, confirming the ability of prions to adapt to new environment, a hallmark of Darwinian evolution. When they returned to the brain, brain-adapted prions again took charge of the population.

To confirm the results and to study the question of the evolution of drug resistance, Weissmann and his colleagues used the drug swainsonine or SWA, which is found in plants and fungi, and has been shown to inhibit certain strains of prions. In crops where the drug was present, the team discovered that the sub-strain of drug-resistant prion evolved to become predominant. When the drug was withdrawn, the sub-strain susceptible to swainsonine increased again to become the main component of the population.

Weissmann noted that findings have implications for developing therapeutic targets for prion diseases. Instead of developing drugs to target abnormal proteins, might be more efficient to try to limit the supply of prions normally produced essentially reduce the amount of fuel feeding the fire. Weissmann and his colleagues have shown some 15 years ago that genetically modified mice lacking normal prion protein develop and function in a completely normal (and are resistant to prion diseases!).

“It’s probably very difficult to pharmacologically inhibit the production of a natural protein specific,” Weissmann said, “You can end up interfering with other critical physiological processes, but nevertheless find a way to inhibit the production of normal prion protein is a project currently pursuing in collaboration with Professor Corinne Lasmezas of Scripps Florida in our department. ”

Quasi-species

Another consequence of the results, the study is that drug-resistant variants exist or prions in the population at a low level before exposure or generated during exposure to the drug. In fact, researchers found that some of prions secreted by infected cells were resistant to the drug before exposure, but only at levels below one percent.

Scientists show that variants of the prion constantly arise in a particular population. It is believed these variants or “mutant” differ in the way in which the prion protein folds. As a result, populations of prions are in fact composed of multiple sub-strains.

This, Weissmann said, is reminiscent of something he helped to shape some 30 years ago, the evolutionary concept of quasi-species. The idea was conceived by Manfred Eigen, a German biophysicist, who won the Nobel Prize in Chemistry in 1967.

This basically a quasi-species is a complex population, which perpetuates itself and various related entities that act as a whole.
Weissmann was, however, who provided the first confirmation of the theory through the study of a particular bacteriophage-a virus that infects bacteria-while he was director of the Institut für Molekularbiologie in Zurich, Switzerland.

“The proof of the concept of quasi-species is a discovery made 30 years ago,” he said. “We found that the population of RNA viruses, which was thought there was only one sequence, was constantly creating and removing unfavorable mutations. In these quasi-populations, as we found in prions, begin with a single particle, but it is very heterogeneous when it becomes a larger population ”

There are some unknown dynamics acting on the prion population that leads to this heterogeneity, Weissmann said, still to be explored.

“It’s amazing that something we did 30 years ago has returned to us,” he said. “But we know that mutation and natural selection occurring in living organisms and now we know that also occur in a non-living. I guess if I could do would not stand much chance of surviving her.