AMEDYST

Dystonia is a motor disorder characterized by muscle contractions causing abnormal postures and/or movements, which are disabling and painful in severe forms. Dystonia can be isolated, or associated with other neurological diseases, including Parkinson's disease, in combination with other motor disorders. The possibilities of medical treatment remain limited. The pathophysiologic mechanisms of dystonia would involve a combination of physiological abnormalities in the basal ganglia and cerebellum but are still poorly understood. The AMEDYST project examines by complementary approaches in animals and patients, (1) how functional abnormalities of the striatum, the entry structure into the basal ganglia network, generate dystonic movements and postures and (2) how the cerebello-thalamo-striatal pathway amplifies dystonic movements by acting on cholinergic striatal interneurons. The project is mostly based on a model of mice hemizygous for the Gnal gene (Gnal+/-), which mimics the genetic alterations discovered in DYT25 dystonic patients. Gnal encodes the G protein a subunit, Gaolf, stimulating adenylyl cyclase, whose strongest brain expression is found in principal neurons of the striatum. In mice, the Gnal haplo-deficiency reduces striatal cAMP production and disrupts striatal functions, but is not sufficient to trigger dystonia onset. However, dystonia appears when Gnal+/- mice receive a cholinergic agonist, showing that an increase in cholinergic tone is critical to the onset of disease. Our project proposes to identify the effects of acetylcholine in the striatum of Gnal+/- to better understand the mechanisms of dystonia. The striatal cholinergic interneurons are controlled by thalamic afferent neurons, themselves regulated by afferents from the cerebellum. Since compelling evidence shows that disruption of cerebellar output causes dystonia, we shall investigate activity alterations in the various nodes of the cerebello-thalamo-striatal pathway in Gnal+/- mice and determine the motor dysfunction induced by their stimulation or inhibition. To establish whether the pathophysiological processes observed in mice show homology with those in human pathology, the role of cerebellum on the activity of an output structure of the basal ganglia (internal globus pallidus) will be determined by electrophysiological recordings in patients during surgery. Mutations in the adenylyl cyclase type 5 (AC5, encoded by ADCY5), strongly associated to Gaolf in the striatum, cause motor disorders, including dystonia. These mutations are more common than those of GNAL in human pathology and provide the possibility to explore the effect of impaired striatal cAMP pathway on a significant cohort of patients. We test in these patients the involvement of the cerebello-thalamo-striatal pathway by fMRI and we determine how non-invasive magnetic stimulations of cerebellum affect thalamus and striatum. The project gathers researchers working on animal models and patients, as well as experts in physiology of the basal ganglia and cerebellum. This highly complementary consortium is adapted to the study of dystonia and is an asset to shed light on the pathophysiological processes of the disease. Our project will also demonstrate the proof-of-concept of new therapeutic approaches that are needed to treat the disease.