Small Rodent’s Unique Properties Key to Studying Prion Disease
A small rodent called the bank vole may hold the key to a better understanding of rare neurodegenerative prion diseases, according to new research from the University of Toronto.
Joel Watts, a principal investigator at U of T’s Tanz Centre for Research in Neurodegenerative Diseases, recently published research that uses the bank vole’s unique susceptibility to prions to study prion infection — and uncovered a surprising result that may eventually lead to new approaches to treating prion disease.
Prions are proteins that can trigger other proteins in the brain to misfold, thereby spreading and causing neurodegenerative disease. In this way, the spread of prion disease in the brain closely resembles other neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease, which also are caused by misfolded proteins that spread and accumulate in the brain.
While prion disease in humans most often develops sporadically, it can arise via infection, for example in the case of bovine spongiform encephalopathy (also known as “mad cow disease”), which can be transmitted between animals and — in rare cases — to humans.
Prions are species-specific, with each type typically infecting only one species; however, prions from any species can infect the bank vole. This unique susceptibility of the bank vole to all types of proteins makes it an interesting research model to understand prion proteins, and in fact, researchers including Watts study the bank vole and its prion protein to learn more about prion disease and better understand the mechanisms of infection and spread.
“Studying the bank vole prion protein will help to develop tools that will allow us to study the biology of these diseases and hopefully uncover a paradigm for developing new therapeutics,” says Watts, who is also an associate professor in the department of biochemistry at U of T’s Temerty Faculty of Medicine.
In recent research published in the Journal of Neurochemistry, Watts and his team aimed to improve research tools to study prion diseases by generating cell lines that express the bank vole prion protein. They engineered cells to express the highly susceptible bank vole prion protein and then exposed these cells to prions that typically only infect mice and hamsters.
The researchers found that the cells expressing bank vole prion protein became infected with prions from these other species. These results demonstrated that the cell line replicated what happens in real animals and could be used to study this protein.
While bank voles are highly susceptible to prion disease, on the opposite side of the spectrum are people who have a genetic mutation that makes them resistant to prion disease.
In the second part of the study, the research team investigated prion protein with the prion-resistant genetic mutation to determine whether this one genetic change would also make the bank vole prion protein resistant. To their surprise, it did.
“I was surprised by the result. I thought the sequence of bank vole prion protein would override that mutation, but it was the opposite,” says Watts. “Exploiting this discovery to develop therapeutics will be challenging, but the idea that a small genetic change can completely block prion disease, even when you had a really permissive substrate, is very interesting.”
While the study is unlikely to lead to clinical applications in the near future, in the short-term, the research team is using their cell-based model to learn more about how prion proteins misfold and how this contributes to disease, which may identify potential drug targets.
Prion disease is very rare, affecting only one or two people per million each year, but Watts says that the research also has applications beyond prion disease and may help with understanding other neurodegenerative diseases caused by protein misfolding.
“The biology that we study with prion disease is relevant to understanding how similar processes occur in the brains of people with Alzheimer’s disease, Parkinson’s disease and ALS. At the molecular level, they’re all very similar mechanisms of a protein changing its shape, clumping together and causing problems in the brain. The only difference being that these other diseases don’t ever become infectious in the same way that prion disease can,” says Watts.
“Even though prion disease is rare, research into this specific area is certainly justified because of the potential impact it could have on other more common diseases.”