The quest to understand prion diseases
Dr. Valerie Sim uses advanced live-cell imaging to track the progression of these fatal infections.
Story by Roland Lines/Image by Veer
Prion diseases are fatal, infectious diseases that cause the central nervous system to degenerate, resulting in sponge-like holes in the brain. Prion diseases include Creutzfeldt–Jakob disease (CJD; a human prion disease) and bovine spongiform encephalopathy (BSE; also known as “mad cow disease”). CJD is relatively rare—it is estimated that 35 new cases are diagnosed in Canada each year—and Dr. Valerie Sim has seen three cases of CJD since arriving in Edmonton in 2009. Witnessing the devastating effects of CJD firsthand is what motivates Dr. Sim’s research into the progression of prion diseases.
Prion diseases have no known cure and seem to be caused by infectious prion proteins. “It’s not like any other living thing that we know about,” Dr. Sim says regarding these prion proteins. In its normal form, prion protein is not infectious and doesn’t cause disease. “The prion protein exists normally in every person,” explains Dr. Sim. “But it can be corrupted, and basically its structure is changed into a form that can cause disease.”
When a prion protein becomes misshapen, it can recruit other normal prion proteins, corrupt their shapes, and cause them to clump together. “It seems to form this chain reaction where you get a bit of abnormal prion protein that bumps into another normal prion protein and makes it abnormal,” explains Dr. Sim. “That’s how the disease spreads and progresses.”
Dr. Sim spends most of her time in her lab at the University of Alberta’s Centre for Prions and Protein Folding Diseases, which was established in 2006. She describes her lab setup as “prion disease in a dish.” She and her team add infectious prion protein to slices of living brain tissue in an incubator and track the progression of the disease using advanced live-cell imaging technology.
“The infection becomes apparent after three to four weeks,” says Dr. Sim. “After that we expect to see some of the changes. We would go in and take a snapshot every week or every day, as needed. The idea is to keep the slice alive while we take the picture, then put it back in the incubator to recover, and then take a look at the same slice again a few days later.”
Healthy nerve cells have small bumps on them called dendritic spines. These spines, which are involved in the transfer of nerve signals from one nerve cell to another, are lost early in prion disease. Dr. Sim is particularly interested in how changes in the structure of these nerve cells are related to the location, size, and density of prion aggregations. For example, do nerve cells lose their spines only after coming into contact with infected prion proteins?
“We expect the spines to decrease in number, and we want to look at the proximity of those changes to accumulations of prion protein,” says Dr. Sim. “Does there have to be direct contact between the clumping prion protein and the changes in the spines, or can you have an accumulation of prion protein over here and have spine loss way over there?”
In the future, Dr. Sim expects the laboratory system to be helpful in testing possible prion disease treatments. “As we see this disease develop, we can more directly intervene to screen different agents or compounds that might have some effect. It gives us a better system to answer the specifics of how a treatment might be working. I think it will be a great system for exploring treatments.”