Parkinson’s disease is a neurodegenerative disorder caused by the death of nerve cells that make dopamine. To combat this loss, doctors currently use levodopa, a drug that is a precursor to dopamine.
In the short term, Levodopa is beneficial, but in the long term it causes dyskinesia in some patients, causing involuntary and irregular movements such as spasms, agitation, head shaking or body swaying. Even if the patient stops taking Levodopa for a certain period, the dyskinesia quickly returns once these patients start taking the medication again.
A new approach to combating dyskinesia
In a new study published in the Journal of Neuroscience on June 26, researchers at the University of Alabama at Birmingham took a different approach to dyskinesia and treated it as “bad motor memory.” They found that blocking a protein called activin A could stop dyskinesia symptoms and effectively erase the brain’s “bad memory” response to some Parkinson’s treatments.
“Instead of looking for a completely alternative treatment, we wanted to see if there was a way to prevent dyskinesia from developing in the first place, and if dyskinesia did not occur, patients could stay on Parkinson’s medication longer,” said David Figg, Ph.D., lead author of the study and assistant professor in the Department of Pathology at the University of Alabama at Birmingham, according to EurekAlert.
Does the brain forget its previous treatment history?
Given the overlap between motor and behavioral memory, the team decided to treat dyskinesia as a bad memory. They found a way to make the brain forget its previous medication history, which would allow them to prolong the effectiveness of levodopa for treating Parkinson’s.
“It appears that the brain was forming a motor memory, and each time the patient received levodopa, this memory was recalled with each subsequent exposure to levodopa,” says Dr. Karen Gunarajus, assistant professor in the Department of Neuroscience at the University of Alabama at Birmingham.
The researchers first studied the striatum – a brain region important for motor control – to see which cells were storing the “bad motor memory.”
The most pronounced changes were in neurons called D1 medium spiny neurons, which behaved in a similar way to neurons in the hippocampus when forming a memory. The hippocampus is a complex brain structure that plays a key role in learning and memory.
“We found that some of these neurons were expressing genes that indicated they were being activated by levodopa, and genes that were necessary for making new connections with other cells,” Vij said. “This was very similar to what happens when you learn something new and recall that memory.”
Blocking of actifin A protein
The researchers found that a single gene in these neurons activated by levodopa translates into a protein called activin A. By blocking the function of activin A, the researchers were able to block the development of levodopa-induced dyskinesia in mouse models.
“By blocking the protein from working, we were able to stop the development of dyskinesia symptoms in mouse models, erasing the brain’s memory of the motor response to levodopa,” says Gunaraj.
The team hopes that these findings will lead to an understanding of how to completely block these bad motor memories and eliminate the symptoms associated with dyskinesia in Parkinson’s patients.