University of Ottawa builds a better mouse for Parkinson’s research

Karen Chen

Ottawa Citizen - OTTAWA — University of Ottawa researchers have published a study about a mouse — a mouse that could lead to a better understanding and better treatments for Parkinson’s, the neurodegenerative disease characterized by the gradual loss of motor control.

The study, published in the American journal Proceedings of the National Academy of Sciences on Sept. 10, introduced an animal model that for the first time mimics the way the disease progresses in humans.

For years Parkinson’s researchers were stuck with a conundrum: Clinical trials involving humans were often spectacular failures and attempts to manipulate the same genes that cause symptoms in humans often had no effect in animals.

Parkinson’s affects a specific part of the brain, targeting around 400,000 dopamine-producing neurons in a pea-sized area called the substantia nigra that controls movement. The disease gradually causes those neurons to deteriorate, which leads to the restricted and uncontrolled movement like the familiar hand tremor.

“If you don’t have a system that really models what happens in humans it’s very difficult to study,” said David Park, co-director of the Ottawa based Parkinson’s Research Consortium and the lead author of the study. “How do you study a degenerative process if you can’t get things to degenerate?”

The mouse that stars in the University of Ottawa study solves that conundrum.

Some causes of Parkinson’s are known and others are not. One gene, called DJ-1, is known to cause Parkinson’s in humans when it is either missing or mutated. Five years ago, Park and his team started collaborating with University of Toronto researchers Tak Mak and Raymond Kim, who first tried to remove the DJ-1 gene a mouse. Nothing happened; the mouse seemed unaffected.

Following the disappointing results, many scientists turned their energy to the biochemistry related to Parkinson’s, still without a good model to test theories. Park’s team, which at the time included Maxime Rousseaux and Paul Marcogliese, persisted with the mouse model, determined to come up with a population homogeneous enough and genetically pure enough for the gene manipulation to work.

After they felt the particular strain was pure enough, they tried knocking out the DJ-1 gene again. This time, success. They tested the modified mice by putting them on a metal grid and timing how long the mouse could hold on as the grid turned. Mice that had been manipulated couldn’t hold on for 60 seconds, something unmanipulated mice used as a control had no problem doing.

Even more significantly, the motor control symptoms of the manipulated mice deteriorated over time, getting progressively worse as they aged, just like humans.

“We’re symmetrical: we have two hands and two feet. The brain is kind of similar, and what happens is that degeneration starts on one side and then goes to both sides,” Park said. “So earlier you see things happen on one side (of the body) and then eventually both sides go, and this is what we were seeing in this mouse.”

With a robust animal model that can consistently replicate the symptoms and progression of Parkinson’s, the mouse provides researchers with a sample to test their theories. For instance, if a scientist hypothesizes that a particular brain signal triggers the DJ-1 gene to degenerate, they can see how the mouse reacts. This is important because historically, Parkinson’s treatments have focused on symptoms instead of prevention or potentially stopping degeneration.

Parkinson’s “is one of those diseases where you can provide symptomatic treatment but eventually parts of your brain keep deteriorating and those symptomatic interventions no longer work,” Park said. “It’s devastating.”

On top of that, the mouse allows researchers to examine early stages of Parkinson’s that are hard to find in humans because patients rarely visit a physician if they have no visible symptoms, even though severe mental deterioration has already begun by the time most Parkinson’s patients are diagnosed. The advantage of testing the mouse is that researchers can locate and identify the best time for a potential treatment and then practise more targeted clinical studies when they eventually involve humans. Studying the mouse will allow scientists to know whether to study patients who are in early stages of Parkinson’s, or who have had it for years, or those who have not been diagnosed but are likely to have it because of family history.

The mouse is not the cure, but it may the vessel that will lead researchers there.

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