While L-DOPA (levodopa) is the most effect treatment available for Parkinson’s disease, it commonly leads to dyskinesia – a poorly-understood side-effect characterized by uncontrolled muscle movement – which can be just a difficult to deal with as the disease itself. Researchers at the Columbia University Medical Center (CUMC) have identified the mechanism by which L-DOPA causes dyskinesia.
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, and his colleagues used a mouse model of the disease, along with a newly-developed method for manipulating neurons to study the action of L-DOPA on the brain. Their main finding was that when striatonigral neurons became less responsive to the inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), development of dyskinesia was the result.
Since the specific type of neuron involved in development of the movement disorder was identified, the researchers hope that these brain cells could be manipulated in order to prevent or postpone the side-effect of L-DOPA. Results from the study were published online in the journal, Neuron.
Parkinson’s disease is the result of a dopamine shortage caused by the death of the cells that secrete the neurotransmitter, in a region of the brain known as the substantia nigra. A lack of dopamine leads to the abnormal firing of neurons, which results in a reduction in movement control.
“While Parkinson’s is not curable, it is treatable with L-DOPA, which is converted into dopamine in the brain,” said Sulzer. “However, while taking L-DOPA helps patients move normally, in many individuals it eventually triggers uncontrolled excessive movements.” It is estimated that Parkinson’s disease affects one million individuals throughout the US, and as many as 10 million people worldwide.
Though other studies have attempted to elucidate the main cause of dyskinesia by studying the dopamine receptors still present in the brain of a Parkinson’s patient, these neurons become hyper-reactive to treatment with L-DOPA. In the present study, the researchers studied the effect of dopamine deficiency on the neurons in the basal ganglia of the brain, and how they regulate movement.
“Dopamine neurons modulate the basal ganglia, 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,” said Anders Borgkvist, PhD, a postdoctoral fellow in Dr. Sulzer’s laboratory, and the paper’s lead author.
Before now, there was no technique available to study what effects the lack of dopamine had on specific cells of the basal ganglia. The team at Columbia used optogenetics – a unique branch of genetics that utilizes light as a molecular control over neurons that have been genetically sensitized to light – and found that long-term dopamine shortage led to striatonigral neuron insensitivity to GABA. This result was unique to long-term loss of dopamine, and was not observed when dopamine was depleted for a short period of time.
“When striatonigral neurons are working normally, they act as a brake on the basal ganglia, in effect shutting down unwanted movement,” said Sulzer. “But when there is dopamine loss, as in Parkinson’s, striatonigral neurons try to compensate, and eventually lose their responsiveness to GABA. Our hypothesis is that when L-DOPA is added into the system, you lose the ability to filter, or turn off, unwanted movement.”
“Our findings suggest that GABA and GABA receptors are still present in the striatonigral neurons,” commented 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.”
According to Dr.Stanley Fahn, the H. Houston Merritt Professor of Neurology and emeritus director of the Parkinson’s Disease Foundation Research Center at CUMC, “Patients do not develop dyskinesias in the early stages of Parkinson’s, but only after several years of the disease. A major reason why these patients want to delay the initiation of L-DOPA therapy is to avoid these dyskinesias for as long as possible. These new findings open up possible ways to treat or prevent the dyskinesias. If such treatments were found, patients would probably seek to be treated early and improve their quality of life sooner.”
- Major complication of Parkinson’s therapy explained – http://www.sciencedaily.com/releases/2015/09/150910131928.htm
- Borgkvist, A., Avegno, E., Wong, M., Kheirbek, M, Sonders, M., Hen, R., and Sulzer, D. (2015) Loss of Striatonigral GABAergic Presynaptic Inhibition Enables Motor Sensitization in Parkinsonian Mice. Neuron.