Preventing a cure from becoming as bad as the disease

VGluT3 in serotonin neurons and its role in L-Dopa-induced Dyskinesia

Martin Parent
Laval University
Pilot Project Grant
$45,000 over 2 years

The drug levodopa, or L-Dopa, remains the most effective and widely prescribed treatment for the symptoms of Parkinson’s disease, but its side effects include involuntary movements called dyskinesia that can be more debilitating than the underlying disease.

Dr. Martin Parent, an associate professor at Laval University’s Department of Psychiatry and Neuroscience, is examining the causes of this unwanted interaction with an otherwise valuable drug.

“We estimate that maybe 70 percent of patients will have dyskinesia after five or six years of treatment,” he says. “That’s a big problem.”

The heart of this problem appears to be the brain’s response to Parkinson’s, which reduces the number of healthy axons, the long, thread-like part of nerve cells in the brain that control movement. As axons disappear, they are steadily replaced by cells that do not function in the same way. These new cells are responsible for distorting the effectiveness of a key medication.

“They take the L-dopa and then release dopamine in an uncontrolled way,” says Parent. These bursts of dopamine flooding into the brain are reflected in the similarly uncontrolled movements associated with dyskinesia.

Parent and his colleagues have traced this behaviour to a particular gene called VGluT3, which he pronounces “Vee Glute Three.” Now, they’re examining mice that have been genetically altered to prevent this gene from functioning, to see if that prevents dyskinesia from occurring in the presence of levodopa.

Parent is also excited about using cutting-edge gene-editing technology, called CRISPR-Cas9, to “knock out” or remove this gene. This innovative approach, which has only been developed in the last couple of years, uses a virus to knock out VGluT3 in adult mice, something that was not previously possible. The technology results in a less cumbersome, more cost-effective process, so Parent expects this approach to accelerate the research.

Above all, Parent hopes his findings will help ultimately help researchers and clinicians understand and overcome the challenge of using levodopa to benefit people with Parkinson’s.

“There are drugs that limit dyskinesia by decreasing the effect of L-Dopa, but that doesn’t leave a patient any better off,” he says. “By acting directly on the target gene, VGluT3, we hope we’re going to have more success in clinical trials.”