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drs. figge and jaunarajsCommon treatments for Parkinson’s disease, a neurodegenerative disorder that affects an estimated 1 million people in the U.S. and 10 million worldwide, address short-term symptoms. However, in the long term, these treatments can cause extensive problems for patients, namely in the form of uncontrollable movements and postures called dyskinesia.

A recent study published by UAB researchers in the departments of Neurology and Pathology has revealed that approaching dyskinesia the same way the brain reacts to a “bad memory” could lead to a way to halt its progression and in turn, better treat the disease.

A memory-related methodology

The study, published in The Journal of Neuroscience and authored by David Figge, M.D., Ph.D., Henrique de Amaral Oliveira, M.S., Jack Crim, B.S., Rita Cowell, Ph.D., David Standaert, M.D., Ph.D., and Karen Jaunarajs, Ph.D., was inspired by an interest in finding new and better treatments for Parkinson’s disease, a neurodegenerative disorder caused by the death of the neurons that make dopamine.

To replace that lost dopamine, clinicians currently use L-DOPA, a drug that is a precursor to dopamine. Short-term, L-DOPA is helpful, but long term, it leads to L-DOPA-induced dyskinesia in some patients, which causes involuntary, erratic movements such as twitching, fidgeting, head-bobbing, or body swaying. Even if a patient stops taking L-DOPA for a certain period, dyskinesia has proven to come back quickly—as soon as these patients restart treatment.

“It almost seemed like the brain was forming a motor memory and that, each time a patient received L-DOPA treatment, this memory was then recalled upon every subsequent L-DOPA exposure,” Jaunarajs said. “Due to these overlaps between motor and behavioral memory, we wondered if we approached dyskinesia like a bad memory, could we find ways to cause the brain to forget its previous treatment history and provide a way to prolong the usefulness of L-DOPA for Parkinson's treatment.”

Delving into dyskinesia development

Thinking about L-DOPA-induced dyskinesia from a memory perspective led researchers to wonder which cells in the striatum, the brain region significant to motor control, are storing this “bad motor memory” in Parkinson’s disease patients.

As the epicenter of where dyskinesias start in the brain, the striatum was the first place to explore gene expression among specific types of cells. Researchers used single-cell RNA sequencing to identify gene expression changes in more than 100,000 individual cells and their involvement in dyskinesia development. The most significant changes observed were in neurons called D1-MSNs, which acted in a similar way to neurons in the hippocampus when it is forming a memory.

“We found that some of these D1-MSNs were expressing genes indicating that they were being activated by L-DOPA and genes that were necessary for creating new connections with other cells,” Figge said. “This was very similar to what happens when you learn something new and recall that memory.”

Blocking ‘bad motor memories’

Researchers found that one gene in particular in these L-DOPA-activated D1-MSN neurons is translated into a protein called Activin A, which led to promising results.

“By blocking the function of Activin A, we were able to block the development of L-DOPA-induced dyskinesia in our mouse model,” Jaunarajs said. “These data really highlighted a previously unappreciated pathway that could potentially be targeted to prolong L-DOPA’s usefulness for Parkinson’s disease patients.”

In essence, by prohibiting the protein from functioning, researchers were able to halt the development of dyskinesia symptoms in their mouse model – effectively erasing the brain’s memory of the motor response to L-DOPA.

“Furthermore, we noticed that initially lots of cells were activated by L-DOPA treatment; however, after repeated exposures, the number of these activated D1-MSNs actually went down,” Figge said. “Although this seems a little backward, this is a lot like what happens when you learn something new: initially, many cells are required to form a memory; however, as you get better at recalling the memory, your brain gets more efficient and fewer cells are necessary to quickly retrieve it.”

Next steps in research

Having posited a new way of thinking about L-DOPA-induced dyskinesia, scientists in this study hope their findings can be used as a resource for the greater research community to further understand how the brain’s regulatory regions contribute to the development of the memory related to L-DOPA treatment.

Ultimately, the hope is that these findings will lead to an understanding of how to block these bad motor memories altogether—eradicating dyskinesia-related symptoms in Parkinson’s patients.

“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,” Jaunarajs said.

This study was supported by the Parkinson Association of Alabama, the American Parkinson Disease Association, and the Department of Defense.