R01 Grant Funds Research of Levodopa-Induced Dyskinesia in Parkinson’s

Fredric Manfredsson, PhD, a neuroscientist at Barrow Neurological Institute, has received an R01 grant from the National Institutes of Health to support his research on a side effect of Parkinson’s disease medication known as levodopa-induced dyskinesia.

The grant will provide about $3.2 million in funding over five years to Dr. Manfredsson and his co-investigators: Christopher Bishop, PhD, at Binghamton University in New York and Keui Tseng, MD, PhD, at the University of Illinois Chicago.

“The three of us have worked on this for many years and have converged on very similar findings: that the serotonin circuit in the brain changes and facilitates the genesis and maintenance of this side effect,” Dr. Manfredsson said.

The Challenge: Levodopa-Induced Dyskinesia Complicates Disease Management

Levodopa remains the gold-standard therapy for Parkinson’s disease. Nicknamed L-DOPA, this medication alleviates movement-related symptoms of Parkinson’s disease by replenishing dopamine in the brain.

Dopamine plays an important role in communication between nerve cells. While the chemical messenger is often associated with mood, it facilitates other functions including movement. Parkinson’s disease causes the neurons that produce dopamine to gradually deteriorate and die.

Like virtually all medications, levodopa can cause side effects. One of the most problematic is dyskinesia, which describes an involuntary muscle movement.

Approximately 90 percent of patients develop levodopa-induced dyskinesia (LID) within a decade of taking the medication. The side effect can range from bothersome to debilitating.

Dyskinesias can be various movements, from bobbing of the head and flailing of the arms to severe twisting and writhing of the body. These uncontrollable movements can last for minutes or even hours. 

“LID increases in severity as you continue levodopa treatment, and it really complicates the management of the disease,” Dr. Manfredsson said. “Patients understandably become fearful of taking their medication.”

The Findings: Serotonin Circuit Linked to Levodopa-Induced Dyskinesia

While studying levodopa-induced dyskinesia independently of one another, Dr. Manfredsson and Dr. Bishop both discovered a separate network of nerve cells that appeared to be responsible for the side effect: the serotonin circuit.

“Which is quite groundbreaking to discover, because it has nothing to do with the actual loss of neurons that happens in Parkinson’s,” Dr. Manfredsson said.

Serotonin is a chemical messenger also involved in mood, as well as other functions like sleeping and eating. Serotonin-producing neurons can convert levodopa to dopamine.

The researchers’ findings suggested that the serotonin circuit rewires itself in an attempt to compensate for the loss of dopamine neurons, but it forms its new connections incorrectly—a phenomenon known as maladaptive plasticity.

Brain plasticity isn’t always a bad thing. The brain constantly changes to learn new tasks and form new memories. When someone sustains a traumatic brain injury, neuro-rehabilitation harnesses the power of plasticity to help patients regain lost functions.

But plasticity can cause problems when the rewiring is faulty. Maladaptive plasticity is the primary suspect behind phantom limb syndrome, in which people feel pain in limbs that have been amputated.

“We also think this behavior is a proxy of some of the other non-motor symptoms that happen in Parkinson’s, like psychosis, impulse control disorders, and cognitive problems,” Dr. Manfredsson explained. “We think these same kinds of plasticity changes may have some contribution to those symptoms as well, so this grant is a really good first step.”

The Goal: Getting Granular, Identifying Therapeutic Targets

Dr. Manfredsson and his team feel confident that these serotonergic circuity changes are the culprit behind LID, but the grant will allow them to explore how and why these changes occur—and where they can intervene.

Each researcher comes from a different school of neuroscience. Dr. Manfredsson’s expertise is in molecular biology and gene therapy. He studies the structure of and interactions between cellular molecules, and he develops viral vector-based tools to therapeutically alter the genes within cells.

Dr. Bishop brings experience in pharmacology—the study of drugs and how the body responds to them. He is also a behavioral neuroscientist, who examines the biological basis of human behavior. Dr. Keui measures the electrical properties of cells as an electrophysiologist.

“Together, we’ll be able to create a comprehensive picture of what’s really going on,” Dr. Manfredsson said.

The researchers will use a human model, consisting of postmortem tissue, and a rodent model to investigate the abnormal neuroplasticity that occurs during LID and then attempt to correct it.

“We’re going to focus on the role of this serotonergic circuity and how that circuity is causing these symptoms,” Dr. Manfredsson said. “Because if it holds true, and we can start identifying this, it gives us a completely new therapeutic target. Serotonin neurons will respond to different types of medications.”

In fact, the team has already identified potential drug candidates. These drugs have approval from the U.S. Food and Drug Administration (FDA) for other purposes, meaning they could be tested in late-stage clinical trials.

The researchers hope this project will lay the groundwork for treatment strategies that could improve the quality of life for millions of current and future patients with Parkinson’s disease.

“At the end of the day,” Dr. Manfredsson said, “it’s important for people to recognize that Parkinson’s is so much more than just motor symptoms.”