A key mechanism underlying dyskinesia in people with Parkinson’s disease has been uncovered for the first time, potentially paving the way to treat the side effect, it has been announced.
Research by an international collaboration led by Scripps Research, Florida, USA, and involving scientists in Italy, found that people develop jerky, uncontrollable body movements, following dopamine therapy, due to the unintended boost of the protein Ras-guanine nucleotide-releasing factor 1 (RasGRP1), which produces a cascade of effects that lead to L-DOPA-induced dyskinesia (LID).
The team was co-led by Dr Srinivasa Subramaniam, associate professor of neuroscience at Scripps Research and Dr Alessandro Usiello, of the University of Campania Luigi Vanvitelli, Caserta, and the Behavioural Neuroscience Laboratory at Ceinge Biotecnologie Avanzate, Naples.
They established in dopamine-depleted mice and other animal models that inhibiting production of RasGRP1 in the brain during dopamine replacement diminished the involuntary movements without negating the useful effects of the dopamine therapy.
It means there is potential for a new path to easing Parkinson’s dyskinesia while allowing maintenance of dopamine replacement therapy, the team write in the latest edition of Science Advances.
Dr Subramaniam said: “Parkinson’s patients describe treatment-induced dyskinesia as one of the most debilitating features of their illness. These studies show that if we can down-regulate RasGRP1 signalling before dopamine replacement, we have an opportunity to greatly improve their quality of life.”
Levodopa is often used for dopamine replacement therapy, which the brain converts into dopamine. At proper doses, this resolves the symptoms, but if the dose increases and it is used for a longer time, dyskinesia can develop. After a decade, about 95% of Parkinson’s patients will experience some degree of involuntary dyskinesia.
“There is an immediate need for new therapeutic targets to stop LID, or L-DOPA-induced dyskinesia in Parkinson’s disease,” said Dr Subramaniam. “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.”
The next stage of research will examine the best route to selectively reduce expression of RasGRP1 in the striatum while not affecting its expression in other areas of the body.
Subramaniam, Usiello, Eshraghi M et al. RasGRP1 is a causal factor in the development of L-DOPA-induced dyskinesia in Parkinson’s disease. Science Advances 1 May 2020; doi: 10.1126/sciadv.aaz7001
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