title: The neural substrates of rapid-onset Dystonia-Parkinsonism.
abstract: Although dystonias are a common group of movement disorders, the mechanisms by which brain dysfunction results in dystonia are not understood. Rapid-onset Dystonia-Parkinsonism (RDP) is a hereditary dystonia caused by mutations in the ATP1A3 gene. Affected individuals can be free of symptoms for years, but rapidly develop persistent dystonia and Parkinsonism-like symptoms after a stressful experience. Using a mouse model, we found that an adverse interaction between the cerebellum and basal ganglia can account for the symptoms of these individuals. The primary instigator of dystonia was the cerebellum, whose aberrant activity altered basal ganglia function, which in turn caused dystonia. This adverse interaction between the cerebellum and basal ganglia was mediated through a di-synaptic thalamic pathway that, when severed, alleviated dystonia. Our results provide a unifying hypothesis for the involvement of cerebellum and basal ganglia in the generation of dystonia and suggest therapeutic strategies for the treatment of RDP.
authors.affiliation: Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: D Paola
authors.initials: DP
authors.lastname: Calderon
authors.forename: Rachel
authors.initials: R
authors.lastname: Fremont
authors.forename: Franca
authors.initials: F
authors.lastname: Kraenzlin
authors.forename: Kamran
authors.initials: K
authors.lastname: Khodakhah
mesh_terms: D000818:Animals; D001479:Basal Ganglia / Q000502:physiology / Q000503:physiopathology; D002531:Cerebellum / Q000502:physiology / Q000503:physiopathology; D004195:Disease Models, Animal; D020821:Dystonic Disorders / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy; D004569:Electroencephalography; D004791:Enzyme Inhibitors / Q000378:metabolism; D006801:Humans; D051379:Mice; D009043:Motor Activity / Q000502:physiology; D009434:Neural Pathways / Q000033:anatomy & histology / Q000473:pathology / Q000502:physiology; D009474:Neurons / Q000378:metabolism*; D010042:Ouabain / Q000378:metabolism; D011187:Posture; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013312:Stress, Physiological
chemical_list: D004791:Enzyme Inhibitors; D010042:Ouabain; D000254:Sodium-Potassium-Exchanging ATPase