By inhibiting the activity of the Activin A protein, scientists successfully stopped the progression of dyskinesia symptoms and erased the brain’s negative response to L-DOPA treatments.
Common treatments for Parkinson’s disease can manage immediate symptoms but may also lead to serious issues for patients in the long term. Specifically, these treatments can result in dyskinesia, characterized by involuntary movements and postures.
In a recent study disclosed in The Journal of Neuroscience, researchers from the University of Alabama at Birmingham approached dyskinesia differently by considering it as a “negative motor memory.” They discovered that inhibiting a protein called Activin A could effectively prevent dyskinesia symptoms and erase the brain’s negative memory response to specific Parkinson’s treatments.
“Instead of searching for a completely different treatment, we aimed to investigate if there was a way to prevent dyskinesia from emerging in the first place,” stated David Figge, M.D., Ph.D., the lead author of the study and assistant professor in the UAB Department of Pathology. “If dyskinesia can be avoided, patients might be able to continue their Parkinson’s treatment for a longer duration.”
Parkinson’s disease is a degenerative condition triggered by the demise of dopamine-producing neurons. To counter this loss, clinicians presently use L-DOPA, a precursor to dopamine.
In the short term, L-DOPA is beneficial, however, in the long term, it can lead to L-DOPA-induced dyskinesia in certain patients, resulting in involuntary and erratic movements like twitches, fidgeting, head movements, or swaying. Even if patients discontinue L-DOPA for a period, dyskinesia tends to reappear swiftly upon resuming treatment.
“It appeared that the brain was forming a motor memory, and with each L-DOPA administration, this memory was recalled upon subsequent L-DOPA exposure,” mentioned Karen Jaunarajs, Ph.D., assistant professor in the UAB Department of Neurology.
Given the connection between motor and behavioral memory, the researchers decided to view dyskinesia as a negative memory. If they could find a way to prompt the brain to forget its prior treatment history, it might prolong the efficacy of L-DOPA in Parkinson’s therapy.
The team primarily examined the striatum, a critical brain region for motor function, to identify which cells were storing the “negative motor memory.” The most significant alterations were noticed in neurons known as D1-MSNs, which behaved similarly to neurons in the hippocampus when forming memories.
“We discovered that a subset of these D1-MSNs were displaying genes indicating activation by L-DOPA and genes essential for establishing new connections with other cells,” Figge explained. “This process closely resembled how a new learning is retained and remembered.”
Scientists identified that one of the genes in these L-DOPA-activated D1-MSN neurons translates into a protein known as Activin A. By inhibiting the activity of Activin A, researchers could prevent the development of L-DOPA-induced dyskinesia in mouse models.
“Essentially, by blocking the protein’s activity, we managed to arrest the onset of dyskinesia symptoms in the mouse models, effectively erasing the brain’s memory of the motor response to L-DOPA,” stated Jaunarajs.
The ultimate goal is for these findings to pave the way for insights into how to eliminate these negative motor memories completely, thereby eliminating dyskinesia-related symptoms in Parkinson’s patients.
