A new study led by Antonio Pisani, MD, PhD of University of Rome Tor Vergata, offers new insights into the role of dopamine in DYT1 dystonia. It may also explain why DYT1 dystonia patients vary in their response to dopamine-boosting medications such as levodopa. The work of Dr. Pisani and his group may inspire new drug design efforts targeting RGS9-2, a protein that regulates dopamine signaling in the striatum, part of the basal ganglia. The researchers have shown that activating RGS9-2 may potentially correct the dopamine imbalance in the brain associated with dystonia and other movement disorders.
Here is the background: In the brain, dopamine is one of the major neurotransmitters. It is involved in the control of movement, cognition, affect, and other critical biological functions. In the striatum, dopamine performs two functions: it acts to help execute voluntary movements as well as to prevent unwanted muscle contractions from interfering with voluntary movement. The dual role of dopamine allows for fine-tuning of movement. Disturbances in this system may lead to movement disorders.
The dopamine receptor DRD2, which binds dopamine, regulates the synthesis, storage, and release of dopamine. Lower levels of DRD2 can slow down dopamine production and activity, leading to neurologic effects. For example, the DRD2 receptor levels are lower in DYT1 dystonia as well as in animal models of this disease. It is of note that majority of current antipsychotic drugs, which can trigger movement disorders, target the DRD2 receptor.
Dr. Antonio Pisani and his group discovered that lower levels of the dopamine receptor DRD2 are developmentally correlated with reduction in the RGS9-2 protein, which belongs to a molecular machinery associated with the DRD2 receptor. These changes have direct negative consequences for neurophysiological function of striatal neurons and control of movement. The researchers were able to reverse these negative consequences by experimentally increasing the level of RGS9-2, which restored the levels of DRD2 and its normal function.
The results from this study shed exciting new light on the role of dopamine signaling in DYT1, and may ultimately lead to novel treatment approaches. DMRF is proud to have supported this groundbreaking work,
Bonsi P, Ponterio G, Vanni V, Tassone A, Sciamanna G, Migliarini S, Martella G, Meringolo M, Dehay B, Doudnikoff E, Zachariou V, Goodchild RE, Mercuri NB, D’Amelio M, Pasqualetti M, Bezard E, Pisani A. RGS9-2 rescues dopamine D2 receptor levels and signaling in DYT1 dystonia mouse models. EMBO Mol Med. 2018 Dec 14. pii: e9283
The Dystonia Medical Research Foundation is a 501(c)(3) non-profit organization dedicated to advancing research for improved dystonia treatments and ultimately a cure, promoting awareness, and supporting the well-being of affected individuals and families.