Dystonia is a movement disorder characterized by sustained muscle contractions, frequently causing twisting and repetitive movements, or abnormal postures. Despite the recent progress in understanding how movements are controlled, the neural mechanisms of dystonia remain largely a mystery, and an adequate model is currently lacking. Potential mechanisms include abnormalities in dopamine metabolism, cholinergic function, and striatal dopamine/glutamate interactions. Mutations of the TOR1A gene cause DYT1 dystonia, a common early onset dystonia. This gene encodes torsinA, a member of the """"""""AAA+"""""""" proteins. In studies conducted under the previous period of support, we have found that the mRNA for torsinA is expressed by neurons in several regions of normal adult human brain, including the dopamine neurons of the substantia nigra pars compacta. The expression of the encoded protein is widespread, but is found in presynaptic, putatively dopaminergic terminals in the striatum. In postmortem tissue from individuals with the DYT1 mutation, there are abnormalities of dopamine metabolism suggestive of a defect in dopamine release. We seek funding to extend our anatomical studies, and to investigate the localization and function of torsinA in genetically engineered rodent models. This data is essential to the construction of mechanistic models of the dysfunction, which produces dystonia in general, and DYT1 dystonia in particular.
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