Researchers knew that prions, the misfolded proteins that cause mad cow disease and other brain disorders, were killing off a class of important brain cells in a transgenic mouse model. But when they found a way to rescue those cells, they were astonished to discover the mice still became sick.
Now they believe previous efforts to find the beginnings of the mouse disorder may have been focused on the wrong part of the brain cell and are plotting new directions for research.
In a study that appears in the Jan. 1 issue of the Proceedings of the National Academy of Sciences, scientists report evidence that clinical symptoms in the mice are produced by damage to synapses, the areas where nerve cell branches come together for communication.
"This could have important therapeutic implications," says senior author David Harris, M.D, Ph.D, professor of cell biology and physiology at Washington University School of Medicine in St. Louis. "There's a great deal of effort being put into developing treatments for neurodegenerative disorders that would inhibit neuron death. Our results suggest that if we just prevent cell death without doing something to maintain the functionality of the synapse, patients may still get sick."
Harris notes that the findings also link prion diseases, which are relatively rare, to more common neurodegenerative disorders like Alzheimer's disease, where recent evidence has also elevated the importance of damage to synapses.
Because of the bizarre methods by which prions spread and cause disease, they have only recently gained widespread acceptance as the source of several disorders that rapidly devastate the brains of humans, cows, deer and sheep.
In these disorders, the most infamous of which is mad cow disease, copies of a normal brain protein, PrP, fold themselves into abnormal shapes, dramatically altering the proteins' properties. Genetic mutations can increase chances that copies of the PrP protein will misfold into the prion form. Proximity to prions also can increase the chances that normally folded copies of PrP will misfold and become prions.
Human prion disorders can be caused by inherited mutations, through contamination during a medical procedure or, in very rare instances, from consumption of infected animals. In addition, some "spontaneous" cases of human prion disease currently can't be tracked to any genetic or environmental cause. Human prion disorders have no treatment and are fatal in months to several years.
Harris has created nearly 50 genetically modified lines of mice to study prion diseases. The mouse model that he and his colleagues used for the most recent study has a mutation in PrP that causes it to misfold, leading to difficulty in movement and other symptoms similar to those seen in human prion diseases.
Scientists previously found that the mouse mutation kills off a class of brain cells known as cerebellar granule neurons. They form an important part of the structure of the cerebellum, an area in the back of the brain involved in motor coordination and other functions.