Torsion dystonia is one of the most common and least well understood of movement disorders in humans. Affected individuals manifest contracted, twisting postures due to abnormal neurotransmission of the basal ganglia. This Program is directed towards elucidation of neuronal dysfunction in the early onset form of dystonia, which commences in childhood and can be completely disabling. The DYTl gene responsible for this condition is inherited in an autosomal dominant manner with low penetrance and has been recently cloned by our group. Most cases of this disease are caused by loss of a glutamic acid residue in the carboxy terminus of a novel ATP- binding protein termed torsinA. This gene is expressed selectively and at high levels in dopaminergic neurons in the substantia nigra. TorsinA defines a new gene family with distant relationship to the heat shock/Clp proteins. Our hypothesis is that defects in this protein underlie susceptibility which can lead to diminished release of dopamine into the striatum and, in turn, to altered modeling of neuronal circuitry in the basal ganglia during childhood development. The resulting imbalance in neurotransmission would then affect processing of motor information in this critical region of the brain. Studies are designed to elucidate the role of members of the torsin gene family in this and other forms of dystonia, and to identify other genes which may affect penetrance by linkage and mutational analysis. Brain tissue from human controls and affected individuals, as well as transgenic knock-in mice, will be examined by immunocytochemistry and in situ hybridization to elucidate changes in the distribution and density of proteins involved in neurotransmission, including D1 and D2 receptors. The transgenic mice will also be evaluated for alterations in the development of neuronal connections in the basal ganglia, in behavior and in response to stress. The intracellular distribution of torsinA and the functional effects of the mutant protein will be assessed in cultured dopaminergic neurons and model neural system using immunocytochemistry and a helper virus-free amplicon vector delivery of normal and mutant genes. Cells will be evaluated for functions related to other members of the heat shock/Clp family, including response to heat shock, uptake and release of dopamine, and mitochondrial function. These studies capitalize on the recent identification of the DYTl gene to understand the molecular etiology of early onset torsion dystonia, to elucidate developmental and stress- related plasticity in the basal ganglia, and to provide insights into therapeutic intervention. Given the apparent involvement of dopaminergic neurons in dystonia and Parkinson's disease, these studies should also provide insight into the latter.
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