Heritage Clinical Fellow Dr. Valerie Sim is fascinated by abnormal prion proteins and the diseases they cause.For just over a year the Calgary-raised physician has been doing post-doctoral research in prion disease with a team of world-renowned researchers at the National Institute of Allergy and Infectious Diseases laboratories in Hamilton, Montana. The team investigates the role of prion proteins in causing diseases such as mad cow disease in cows, scrapie in sheep, chronic wasting disease in deer and elk, and Creutzfeldt-Jakob disease in humans.
Dr. Sim and her collaborators at Rocky Mountain Laboratories have shown that size matters when it comes to prions. Abnormal prion proteins will clump together and ultimately form long strands. But the smaller clumps are actually more infectious than the long strands. Individual, unclumped prion proteins are not infectious.
Separating the prion
The research team successfully separated the prion protein particles. It was no easy task. “This particular protein is incredibly difficult to work with because the abnormal form sticks to itself, and the normal form sticks to everything else,” says Dr. Sim. “It’s quite a challenge to get good structural data. That’s why we still have so many unanswered questions about the function of the normal prion protein, and how the abnormal form causes infection and disease. It’s just hard to study.”
The Montana team investigates what happens when prions become folded the wrong way, a phenomenon which is associated with many different diseases. “Once the prion protein is misfolded it’s like a rock: it’s very hard to damage it or unfold it.”
Infection
According to Dr. Sim, if people are exposed to enough malformed prion protein (in contaminated meat, for example) they can become infected with prion disease. Once the prion protein has become abnormally folded, it will infect adjacent normal cells, causing normally-folded prion proteins to fold abnormally as well. Each abnormal prion protein affects the prion protein it comes into contact with, and then that abnormal protein transforms the next normal protein, and so on. This cascade process causes irreversible damage to cells, particularly neurons in the brain. The cells begin to die. A brain infected with prion disease—also known as transmissible spongiform encephalopathies (TSE)—looks rather like a sponge: full of holes.
Abnormal protein deposits are found in the brain in many neurodegenerative conditions, such as Alzheimer’s and Parkinson’s diseases; however, many questions remain concerning what types and sizes of protein deposits are the prime causes of disease. “While prion disease may be relatively rare, what we can learn about how these proteins fold and misfold and cause disease will have tremendous overlap with a lot of the more common neurodegenerative diseases,” says Dr. Sim.
Dr. Valerie Sim is an AHFMR Clinical Fellow who also receives support from the National Institutes of Health (NIH) in the United States. She conducts post-doctoral research at the National Institute of Allergy and Infectious Diseases’ Rocky Mountain Laboratories in Hamilton, Montana, and hopes to return to Calgary to work as a clinician-scientist.
Selected publication
Silveira JR, Raymond GJ, Hughson AG, Race RE, Sim VL, Hayes SF, Caughey B. The most infectious prion protein particles [letter]. Nature 2005 Sep 8;437(7056):257-261.