The motor symptoms of Parkinson’s disease – tremor, inability to initiate movement, rigidity – result from the loss of neurons that secrete the neurotransmitter dopamine. It therefore follows that the best way to treat these symptoms is by replacing a person’s lost dopamine, the strategy behind the drug levodopa. For the first few years, levodopa (also known as L-dopa) effectively helps people with Parkinson’s move more normally. But the longer the therapy is used, patients are more likely to develop a side effect called dyskinesia: abnormal, involuntary movements that are the opposite of Parkinsonian motor symptoms.
Because this dyskinesia is bad enough to severely affect a patient’s quality of life and gives the primary treatment for Parkinson’s a finite shelf life, neurologists are searching for the cause of drug-induced dyskinesia in order to try and stop it.
“This is probably one of the couple most troublesome aspects of an otherwise good therapy,” said Un Jung Kang, professor of neurology and director of the Parkinson’s Disease and Movement Disorders Center at the University of Chicago Medical Center.
Logically, many studies have looked for dyskinesia in the dopamine-related areas of the brain, particularly a region called the striatum (pictured above) where dopamine release is necessary for normal control of movement. Investigators examined the striatum to see if repeated exposure to levodopa causes an unwelcome over-reaction that might produce dyskinesia. But an unexpected finding by two University of Chicago labs suggests that an underdog cell type in the striatum may actually be the source of levodopa’s side-effect scourge.
The study, published last month in PNAS, was conducted using a special mouse model of Parkinson’s disease called aphakia mice, previously featured on the blog in a study of levodopa’s beneficial “long duration response.” Thanks to a naturally-occurring mutation, aphakia mice are born blind and specifically lose their dopamine neurons in the same pattern as the brain changes in humans with Parkinson’s. The genetic mouse model allowed researchers in Kang’s laboratory to study dyskinesia in a more natural form than the traditional mouse model of Parkinson’s, which involves killing dopamine neurons in one fell swoop with a neurotoxin.
Previous research discovered that levodopa increases markers of neuronal activity in the striatum, suggesting that replacing dopamine leads to a hyperactive situation that could mediate dyskinesia. Much of the focus has thus been on the medium spiny neurons that make up about 95 percent of the neurons in the striatum, and are also the cells that directly respond to dopamine. But when Yunmin Ding, a research associate in Kang’s lab, looked at repeated administrations of levodopa, he found that different types of cells, called cholinergic interneurons, were stealing the spotlight.
“Before this, the change was thought to be in medium spiny neurons, and that was the focus,” Kang said. “But contrary to his expectation, Yunmin noticed that the cholinergic interneurons were the ones that actually showed this abnormal gene activation and it correlated much better than what people have observed in medium spiny neurons.”
Cholinergic interneurons release a neurotransmitter called acetylcholine, normally associated with memory and attention. Only about 3 percent of the cells in the striatum are cholinergic, but the cells play a big role in influencing the function of the neurons around them, said Daniel McGehee, associate professor of anesthesia and critical care at the University of Chicago. McGehee’s laboratory, which studies the role of acetylcholine in drug addiction, joined the project to look at how repeated levodopa affects the behavior of these neurons.
Electrophysiology experiments performed by Jon Britt and Austin Lim found that, in line with the gene expression data, cholinergic interneurons were much more active after extended levodopa treatment, making them a prime suspect for promoting dyskinesia. Meanwhile, in mouse experiments performed by Ding and Lisa Won, blocking cholinergic activity reduced dyskinesia after repeated levodopa treatment, suggesting those drugs could help reduce side effects. Experiments duplicated in the older, neurotoxin model of Parkinson’s disease yielded similar results, giving researchers confidence that the findings are likely to be applicable to human disease.
“It is implicating these cells in the development of dyskinesia, so coming up with treatment strategies that interfere with that process could alleviate the unpleasant side effects of an otherwise effective treatment,” McGehee said. “That’s the exciting part.”
In a way, looking back to cholinergic neurons is a return to the early days of Parkinson’s therapy. Before levodopa, anti-cholinergic drugs were actually used to treat Parkinson’s patients and they are occasionally prescribed today, Kang said. However, drugs that interfere with cholinergic transmission have their own set of nasty side effects, producing cognitive issues such as memory problems and confusion.
Understanding more about how increased cholinergic activity in the striatum produces dyskinesia could help researchers find more specific targets that help Parkinson’s patients without creating new symptoms. By eliminating, reducing, or delaying dyskinesia, patients would presumably be able to stay on levodopa for a longer period of time, relieving their Parkinson’s symptoms without suffering from equally disabling side effects.
“We need to really understand the cholinergic interneurons better and develop a better tool for selectively manipulating this system,” Kang said. “The key will be understanding the signal changes within the cholinergic neurons and signals sent downstream to the medium spiny neurons so we have a better appreciation of how to therapeutically target this problem.”
Ding Y, Won L, Britt JP, Lim SA, McGehee DS, & Kang UJ (2010). Enhanced striatal cholinergic neuronal activity mediates L-DOPA-induced dyskinesia in parkinsonian mice. Proceedings of the National Academy of Sciences of the United States of America PMID: 21187382