The Role of Serotonin in Dyskinesias
A new study published in the June issue of Science Translational Medicine reports that an excess of serotonin cells in the tissue transplants used over a decade ago in experimental treatments for PD may be responsible for the onset of dyskinesias, the involuntary movements that are usually associated with dopamine replacement therapy.
The Michael J. Fox Foundation spoke with one of the study authors, Anders Björklund, MD, PhD, of Lund University to learn more about the role of serotonin in dyskinesias and how insight from this study can help in developing effective treatments for people living with Parkinson's disease.
MJFF: Let's start with some background on the tissue transplant studies that led to this research. What were the results?
AB: In clinical trials testing the use of transplanted tissue to replace the dopamine cells that die in PD, a subset of patients developed what are called graft-induced dyskinesias. Of course Parkinson's patients can have dyskinesias for other reasons, namely as a response to L-Dopa treatment. But the dyskinesias experienced by the patients in the tissue transplants studies were seen in the off state -- that is when the patients did not take L-Dopa. So this became a concern and pointed to a new phenomenon that required further research.
MJFF: And further research led to the findings reported in this study? That serotonin may be the culprit?
AB: Actually, the background to this particular study is research that we've been conducting over the last three or four years, funded by the Fox Foundation, focusing on the role of serotonin neurons in the development of dyskinesias in preclinical models of PD. Through these studies, we have become convinced that serotonin can induce dyskinesias and that serotonin neurons were inadvertently included in the tissue transplant preparations, leading to graft-induced dyskinesias. Recently, another group reported a case where they were actually able to count the number of serotonin neurons contained in a patient's transplant. So this confirmed our suspicions that the transplants contained not just dopamine neurons but serotonin neurons as well.
MJFF: So how does the new study shed light on the role of serotonin in graft-induced dyskinesias?
AB: The Science Translational Medicine study looked at two patients that have had their transplants for a very long time and who slowly developed graft-induced dyskinesias. The researchers used two different techniques to study the role of serotonin. The first measured serontonin activity using a particular imaging technique and the second inhibited serotonin neurons to study the effects. The results showed two things. One, that these patients indeed have serotonin hyperactivity in the grafted area. And, secondly, that silencing the serotonin neurons will almost completely block the graft-induced dyskinesia. Taken together, the conclusion from this study is that the serotonin component is an important element in inducing this side effect.
MJFF: How do you think serotonin neurons could be causing dyskinesias?
AB: This is very interesting because it's not serotonin itself that is inducing dyskinesias. What serotonin neurons can do is to take up either dopamine or L-Dopa and release it together with serotonin. So it's still dopamine that is causing the dyskinesias.
MJFF: Does that mean that the results of this study can also be applied to people who have dyskinesias from dopamine replacement therapy?
AB: It adds to the evidence for a role of serotonin neurons in the development of dyskinesias. There is a parallel line of study, which has been supported quite actively by the Fox Foundation, to develop a treatment that could block dyskinesias by silencing serotonin neurons. And we have a Fox Foundation grant to with a US biotech firm to test such a drug in dyskinetic patients. So we think that certain inhibitors are interesting targets for anti-dyskinetic therapy.
MJFF: Do you think that tissue transplants should be performed again?
AB: Yes, this has influenced the discussions on how to continue the transplantation trials in patients. It's generally agreed that the main issue with tissue transplant treatments for PD is to avoid the development of the side effects. Although this study is only in two patients, it points toward a mechanism that makes it possible to avoid dyskinesias with tissue transplantation. So we are now suggesting that future studies should make sure that cell preparations are essentially free of serotonin neurons. In Europe, we are planning for a second round of transplantation studies and will make sure that we don't include any major component of serotonin neurons.
MJFF: What are some other next steps for this area of research?
AB: Remember that this published study is only in two patients. So we are planning to do similar studies on a few more patients to get more evidence. In parallel, we are also doing further experiments to explore the mechanisms underlying this effect and to also test ways to silence the serotonin neurons.