Novel therapeutic target in DYT1 dystonia

What is it about?

DYT1 dystonia is a progressive and highly disabling disease, with symptom onset between childhood and adolescence. Dysfunction of dopamine D2 receptors in the striatum, a brain region involved primarily in motor control and motor learning, has been reported in DYT1 patients and rodent models. Therefore, restoring striatal D2 receptor function represents a potential therapeutic strategy. We investigated the molecular mechanisms of striatal dopamine D2 receptor dysfunction in multiple mouse models of DYT1 dystonia. We found that the striatal levels of D2 receptor, and of its regulatory proteins spinophilin and RGS9-2, are reduced. We show that D2 receptor downregulation is mediated by an abnormal, selective trafficking to lysosomal degradation. Furthermore, we present evidence that viral-induced expression of RGS9-2 is able to restore both the striatal level and the function of dopamine D2 receptor.

Featured Image

Photo by Terry Vlisidis on Unsplash

Photo by Terry Vlisidis on Unsplash

Why is it important?

These results provide an explanation for the lack of effectiveness of dopaminergic drugs in DYT1 dystonia, despite a clear involvement of dopamine receptors in disease pathophysiology. More importantly, our work identifies novel therapeutic targets that are effective in rescuing the dopaminergic dysfunction in DYT1 dystonia.