The mysterious, highly infectious prions, which cause the severe destruction of the brain that characterizes “mad cow disease” and several human brain degenerative disorders, can be rendered harmless in the laboratory by a slight alternation of the three-dimensional conformation or shape of the prion protein’s structure.
The discovery, which opens up new directions for researchers studying the currently untreatable prion diseases in humans and animals, is reported in this week’s Nature by Salk Institute scientist Roland Riek and colleagues, along with collaborators in France and Switzerland.
Riek and his colleagues used a fungus as a model system because its prions are easier to isolate and work with than are the prions from humans and other mammals. “It’s a fantastic system to study the structural components of prions and measure infectivity,” Riek said.
“This discovery is very interesting from a basic scientific point of view because it shows that a specific conformation of the prion protein is the infectious entity, and also that we can easily destroy the prion’s infectivity by altering its shape,” said Riek. “We now need to find out if this is also the case in mammalian prions.”
Identified only about 25 years ago, prions are highly unusual infectious agents that sit on the outside of membranes of the cells of many organisms including the human.
So tiny that they cannot been visualized even with the most powerful microscopes, prion proteins exist in two forms in nature: a normal (non-infectious) shape and the abnormal structure that occurs in mad cow disease, scrapie, kuru and several other brain infections.
Most prion infections begin when the normal shape, for reasons unknown, spontaneously changes into the infectious form that kills brain cells. The infection is spread through a chain reaction like process that begins when the first abnormal prion “tags” a prion that has a normal conformation and forces it to adopt the abnormal prion shape. This new rogue prion joins in the game of “tag,” by forcing another normal prion into the abnormal form.
Previous studies revealed that a prion’s switch from a normal to the infectious form is associated with a change in the three-dimensional folded shape, or conformation, of the prion’s protein structure. Building on research that identified the part of the prion protein that made a fungal prion infectious, Riek and colleagues discovered that this critical region forms a flat structure called a beta-sheet.
Using a genetic engineering technique called point mutation to change one at a time each amino acid component of the prion protein, the Salk scientists created a variety of different versions of the prion to determine whether the flat shape of the beta-sheet itself was necessary for a prion to be infectious.
The Salk team found that destroying the shape of the beta-sheet rendered the prion harmless. It was no longer able to spread throughout the fungal cell and “tag” other prions, causing them to become infectious.
This research opens up new directions for researchers studying prion diseases in humans and other animals, since targeting the beta-sheet shape might turn out to be a strategy for controlling the feared and untreatable brain-wasting prion diseases such as bovine spongiform encephalopathy.
The study also may help to improve our understanding of such neurodegenerative diseases as Alzheimer’s, in which brain cells gradually “silt up” with structures similar to the prion beta-sheet that are connected to brain cell death.
From Salk Institute