TORSIN A AND THE PATHOPHYSIOLOGY OF DYSTONIA Mutations of the DYT1 gene cause early onset torsion dystonia. This gene encodes torsinA, a member of a novel family of proteins with homology to the HSP 100/CLP family of heat shock proteins. In preliminary studies, we have found that the gene for torsin A is active in nerve cells in several regions of normal adult human brain, including the dopamine neurons of the substantia nigra pars compacta. We have also found that the gene is always active in the brains of patients who are ill for more than a day but not in the brains of those who die suddenly. This finding is consistent with, but does not prove, that torsinA is a stress response protein. In this application we seek funding to obtain detailed information about the localization and regulation of the torsinA mRNA and protein in both human brain and genetically engineered rodent models. We will determine exactly which cells in human and mouse brain contain the mRNA and protein, where in the cells the protein is located, whether mRNA expression is regulated by stress and whether the mutation effects the location or amount of mRNA expression, the subcellular location of the protein or the function of dopamine neurons. These data are essential to the construction of mechanistic models of the neural dysfunction which produces dystonia.
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