L-DOPA, a treatment for Parkinson’s disease, may induce dyskinesia
Parkinson’s disease is a neurodegenerative disorder caused by the death of dopamine-producing neurons.
To address this dopamine deficiency, clinicians currently prescribe L-DOPA, a precursor to dopamine.
While L-DOPA is beneficial in the short term, it can cause L-DOPA-induced dyskinesia in some patients over the long term, leading to involuntary, erratic movements such as twitching, fidgeting, head-bobbing or body swaying.
Even if a patient discontinues L-DOPA temporarily, dyskinesia often quickly recurs when treatment is resumed.
It appeared that the brain was creating a motor memory, recalling it with each subsequent L-DOPA treatment.
Given the similarities between motor and behavioural memory, the team decided to treat dyskinesia as if it were a bad memory.
Treating dyskinesia as a ‘bad motor memory’
If they could find a way to make the brain forget its previous treatment history, they might extend the effectiveness of L-DOPA for Parkinson’s treatment.
Researchers began by examining the striatum, a brain region crucial for motor control, to identify which cells were storing the “bad motor memory.”
They observed the most significant changes in neurons called D1-MSNs, which behaved similarly to neurons in the hippocampus when forming a memory.
They discovered that some D1-MSNs expressed genes indicating activation by L-DOPA and the creation of new connections with other cells, similar to the process of learning and recalling new information.
One gene in these L-DOPA-activated D1-MSN neurons was found to translate into a protein called Activin A.
By inhibiting Activin A, researchers successfully prevented the development of L-DOPA-induced dyskinesia in mouse models.
Essentially, by blocking this protein’s function, they could stop dyskinesia symptoms from developing in the mouse models, effectively erasing the brain’s memory of the motor response to L-DOPA.
The ultimate goal is to use these findings to learn how to block these bad motor memories completely, eliminating dyskinesia-related symptoms in Parkinson’s patients.
Karen Jaunarajs, PhD, assistant professor in the UAB Department of Neurology at The University of Alabama at Birmingham explained the key findings to Medical News Today.
“Our goal for this particular study was to lay the foundation for thinking about L-DOPA-induced dyskinesia as a form of bad motor memory by trying to figure out what cells were storing this memory. A lot of work has shown that a brain region important for motor memory, known as the striatum, is pivotally involved in the development of dyskinesias. But the brain is made up of many different types of cells, like neurons, supporting cells, and immune cells, that all respond differently following L-DOPA treatment. Which ones stored the drug history was unknown.”
— Karen Jaunarajs, PhD
“Therefore, the primary goal of this study was to create a map of all the changes in gene expression from all of the different cells in the striatum across the development of L-DOPA-induced dyskinesia: from the first exposure to L-DOPA, to how that response evolves with repeated L-DOPA treatments,” Jaunarajs said.
“We used single-cell RNA sequencing to identify all of the gene expression changes that were happening in over 100,000 individual cells during dyskinesia development. By establishing a comprehensive profile of the changes in gene expression across all of the different types of cells in the striatum, we found that many of the most significant differences were in a certain type of neuron, called D1-MSNs,” she further explained.
“We found that some of these D1-MSNs were expressing genes indicating that they were activated by L-DOPA and genes necessary for creating new connections with other cells. This was very similar to what happens when you learn something new and recall that memory. Furthermore, we noticed that lots of cells were initially activated by L-DOPA treatment; however, after repeated exposures, the number of these activated D1-MSNs decreased.”
— Karen Jaunarajs, PhD
“Although this seems a little backward,” Jaunarajs said, “this is a lot like what happens when you learn something new: initially, many cells are required to initially form a memory, however, as you get better at recalling the memory, your brain gets more efficient and fewer cells are necessary to retrieve it quickly.”
Chandril Chugh, MD, adult and paediatric neurologist based in Patna, India, who was not involved in this research, told MNT that this manuscript “makes for an intriguing read where a common clinical problem of dyskinesias post syndopa treatment has been discussed.”
“The authors have conducted an animal based study and demonstrated how striatal neurons behave after being exposed to dopamine stimulation. This study is helpful in enhancing our understanding of a common disease and enhance patient care and satisfaction.”
— Dr. Chandril Chugh
Potential implications for future Parkinson’s patients
Jaunarajs highlighted several implications of this research.
“First, one of the more exciting genes we found in these activated D1-MSNs is translated into a protein called Activin A. By blocking the function of Activin A, we were able to block the development of L-DOPA-induced dyskinesia in our mouse model,” she said.
“These data highlighted a previously unappreciated pathway that could potentially be targeted to prolong L-DOPA’s usefulness for Parkinson disease patients,” she continued.
“Second, there are hundreds of genes that we have not even investigated yet and we hope that our data can be used as a valuable resource by the wider research community to identify other potentially useful targets for therapy development,” Jaunarajs explained.
“Finally, we hope our results can change the way the research community thinks about L-DOPA-induced dyskinesia, and maybe other types of movement disorders, as the result of bad ‘motor memories’ and use what we know about how the brain functions in learning and memory to inform our research into movement disorders.”
— Karen Jaunarajs, PhD
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