Modulation of striatal cAMP levels: A key pathway in the treatment of hyperkinetic movement disorders

Hyperkinetic movement disorders, like dystonia, chorea, myoclonus, dyskinesia, and tremor, can be extremely disabling, impairing quality of life. Our translational approach in humans and mice investigates the link between cyclic AMP (cAMP) signaling pathway alterations in striatal neurons and hyperkinetic movement disorders. <i>ADCY5</i> encodes adenylyl cyclase 5, key enzyme for striatal cAMP synthesis. Pathogenic variants result in mixed hyperkinetic movement disorders (MxMD-<i>ADCY5</i>). We prove caffeine therapeutic effect in a prospective trial in two patients with MxMD-<i>ADCY5</i> and generated an <i>Adcy5</i> ^<i>R419W</i> mouse model harboring the most frequent human pathogenic variant to understand underlying mechanisms. In patients, movements' severity is increased in absence of caffeine. In mice, caffeine improves motor symptoms through adenosine A_2A receptor blockade. Mutation increases cAMP signaling in striatal projection neurons, an effect selectively corrected by A_2A receptor antagonism in indirect pathway neurons. Fine modulation of neuronal cAMP levels represents a key target to treat hyperkinetic disorders, especially dystonia/dyskinesia.