Study Suggests Mechanism Behind Levodopa-induced Dyskinesia in Parkinson’s

The protein RasGRP1 is a key culprit for involuntary movements that arise from dopamine replacement therapies used to treat Parkinson’s disease, a new study done in animals suggests.

Targeting this protein may be a therapeutic strategy to prevent these motor problems, while still receiving the benefits of treatment.

The study, “RasGRP1 is a causal factor in the development of l-DOPA–induced dyskinesia in Parkinson’s disease,” was published in Science Advances.

Parkinson’s disease is caused by the death of nerve cells in the brain that make the neurotransmitter dopamine. Therapies designed to increase the amount of dopamine in the brain, including levodopa (l-DOPA) and its derivatives, are staples of Parkinson’s treatment.

Although the effectiveness of these treatments is well-established, long-term use is associated with the development of involuntary movements called dyskinesia. However, exactly which molecular mechanisms are responsible for this side effect is not clear.

Previous research implicated a protein called Rhes in the development of  dyskinesia. In the new study, researchers examined the role of a related protein, RasGRP1 (Ras-guanine nucleotide-releasing factor 1). This protein is known to activate Rhes, and it has been shown to be active in certain blood cells. But its role in the brain is less clear.

Researchers first used a mouse model of Parkinson’s in which dopamine-producing neurons are killed by means of a specific toxin (6-hydroxydopamine). The researchers modeled Parkinson’s both in wild-type mice and in mice that had been genetically engineered to lack RasGRP1.

Both types of mice displayed similar Parkinson’s-like symptoms, and l-DOPA treatment resulted in similar improvement in these symptoms in both types. However, mice lacking RasGRP1 displayed significantly fewer abnormal involuntary movements with long-term l-DOPA treatment.

Additionally, in wild-type mice, l-DOPA treatment induced significantly higher levels of RasGRP1 in the mice’s brains. This finding also was replicated in a macaque (a type of monkey) model of Parkinson’s disease.

“Since monkey model for PD [Parkinson’s disease] can mimic more signs and symptoms of human PD, our finding strengthens the translational relevance of RasGRP1 in PD treatment,” the researchers wrote.

Additional biochemical studies indicated that RasGRP1 is involved in dyskinesia through the activation of the proteins mTOR and ERK (as well as other associated proteins).

These proteins have been implicated previously in l-DOPA-induced dyskinesia (LID). However, they play many important roles in different types of cells throughout the body, so it’s difficult to therapeutically target them without significant side effects. In contrast, the lack of functional RasGRP1 in mice did not result in noteworthy physiological problems, apart from some mild deficits related to the development of cells in the thymus, an organ that’s part of the immune system.

Because of this, “… we think that blocking RasGRP1 with drugs, or even with gene therapy, may have very little or no major side effects,” study co-author Srinivasa Subramaniam, PhD, a professor at Scripps Research, said in a press release.

Since mice and humans are biologically distinct in many important respects, further research will be needed to determine the safety profile of treatments intended to block RasGRP1. Nonetheless, this study provides a theoretical foundation for the possible utility of such treatment strategies.

“There is an immediate need for new therapeutic targets to stop LID,” Subramaniam said. “The treatments now available work poorly and have many additional unwanted side effects. We believe this represents an important step toward better options for people with Parkinson’s.”