Groundbreaking research from the University of Alberta has identified the structure of the infectious prion protein — the cause of bovine spongiform encephalopathy (BSE), chronic wasting disease in deer and elk and Creutzfeldt-Jakob disease in humans — which has long remained a mystery.

The infectious prion protein is a misfolded protein, which makes it very difficult to purify and study, the researchers said. Because it clumps together, standard structural biology techniques cannot be used to study it. Since the protein was first purified in the 1980s, researchers have made only limited insights into the structure of the protein.

The collaborative study, published in PLOS Pathogens, used electron cryomicroscopy to collect high-resolution electron micrographs. This was the first time this technology has been used on amyloid fibrils of the infectious prion; these are a special form of clumped-together proteins that form fibrils, the university noted.

"The recent advances to electron cryomicroscopy technology are certainly a breakthrough," said Holger Wille, co-principal investigator and an associate professor in the department of biochemistry with the University of Alberta's Faculty of Medicine & Dentistry. "We know the structure of the healthy normal cellular form of the protein, but we knew very little about the infectious prion protein and how it propagates. The use of these high-powered microscopes has finally given us some clarity."

The team had to develop a processing scheme for the data masses. There were thousands of electron micrographs, and the team had to extract the best images. After three years of working, developing techniques and processing data, the results published in the paper are a three-dimensional model for the structure of the infectious prion protein.

"It is not an atomistic model, so we cannot say which position the atoms are in, but this is something we hope to do in the future," Wille said.

The model can give insights into how the infectious prion protein propagates, he added, noting that the structure argues against existing theories of prion conversion and suggests how the process might actually work. The study suggests how infectious prions replicate by converting non-infectious, cellular versions into copies of themselves.

Moving forward, the researchers want to go into more depth. This study used model system prions, but they are now using the prions that infect cows (BSE), wild animals (chronic wasting disease) and people (Creutzfeldt-Jakob disease).

"Ultimately, if we know how the prion propagates, we could come up with clinical interventions to treat or prevent disease," Wille said.

This research was supported by the Alberta Prion Research Institute and the Alberta Livestock & Meat Agency.

"The Structural Architecture of an Infectious Mammalian Prion Using Electron Cryomicroscopy," was published in PLOS Pathogens online Sept. 8, 2016.