En Route to Better Treatment of Parkinson's

By Jane Farrell

Researchers now know why long-term use of L-DOPA (levodopa), an effective treatment for Parkinison’s disease, causes a problem known as dyskinesia, or excessive movement.

Using a new method for manipulating neurons in a mouse model of Parkinson’s, a Columbia University Medical Center (CUMC) research team found that dyskinesia arises when striatonigral neurons become less responsive to the inhibitory neurotransmitter GABA. This suggests that it may be possible to modify the activity of these neurons to prevent or delay this disabling side effect.

The paper was published in the journal Neuron.

Parkinson’s, a progressive neurodegenerative disorder, results from the death of cells in various parts of the brain, especially in a region called the substantia nigra. It is in the substantia nigra that a neurotransmitter called dopamine is formed, and when dopamine is lacking, neurons fire abnormally, impairing one’s ability to control movement.

“While Parkinson’s is not curable, it is treatable with L-DOPA, which is converted into dopamine in the brain,” said study leader David L. Sulzer, PhD, a professor of neurobiology in the Departments of Neurology, Psychiatry, and Pharmacology at CUMC and a research scientist at the New York State Psychiatric Institute. “However, while taking L-DOPA helps patients move normally, in many individuals it eventually triggers uncontrolled excessive movements.” Parkinson’s is estimated to affect about one million people in the U.S. and up to 10 million worldwide.

According to a news release from Columbia, most studies into the cause of dyskinesia in Parkinson’s have focused on the dopamine receptors that remain in the brain, which over time become over-reactive to L-DOPA therapy. However, the CUMC team decided to look at how neurons of the basal ganglia regulate movement in the absence of dopamine.

“Dopamine neurons modulate the basal ganglia,” explained lead author Anders Borgkvist, PhD, a postdoctoral fellow in Dr. Sulzer’s laboratory. “And because that circuit is still running in patients with Parkinson’s, it’s long been suspected that other parts of the circuit behave abnormally in this disease.”

The CUMC team employed a novel form of optogenetics, a technique that uses light to control neurons that have been genetically sensitized to light, and found that after long-term dopamine loss, striatonigral neurons lose their ability to respond to the neurotransmitter GABA (gamma-aminobutyric acid). This effect was not found with short-term dopamine loss.

“Our findings suggest that GABA and GABA receptors are still present in the striatonigral neurons,” said Dr. Borgkvist. “So then the question becomes, why they aren’t functional? I think that we, or another lab, will eventually find the answer. In any case, the implication is that this defect is correctable, and that would mean that we could prevent or at least delay dyskinesia, so that patients could continue to use L-DOPA.”