Dystonia is a neurologic symptom characterized by sustained involuntary contractions, twisting and turning motions, and postures. While dystonia is a symptom of many other neurologic disorders, DYT-1 dystonia (a.k.a. Torsion Dystonia or Oppenheim's Dystonia) is a primary genetic dystonia. This autosomal dominant disorder is caused by a mutation in a novel Endoplasmic Reticulum (ER)-Iocalized protein named Torsin A that is a member of the AAA family of ATPases. Neither the function of Torsin A nor the consequence(s) of the disease-causing mutation is known. Torsin A is expressed widely throughout the nervous system, but is also expressed in a large variety of non-neural tissues as well. Torsin homologues exist in Drosophila and in C. elegans. The Torsins are most closely related to the Hspl00/CIp family of ATPases whose principal activity is to disaggregate or unfold misfolded proteins for eventual repair or for targeted destruction. We hypothesize that, given that the ER is the major site of protein folding/quality control in the secretory pathway, Torsin A assists in the repair or catabolism of damaged substrates. We have evidence that torsins may be involved in handling unfolded proteins in the ER and now propose to undertake biochemical and genetic approaches in parallel to test our hypothesis. Specifically, we will perform structural, functional, and enzymatic analyses of recombinant torsin A that we produced and purified, identify torsin interacting proteins in the ER, test whether torsin alters the kinetic of removal of proteins from the ER, and will further our C. elegans work both to test our hypothesis and to eventually develop an animal in which we can perform forward genetics to identify other genes in the torsin pathway. My graduate work concerned the mechanism by which proteins are imported into the endoplasmic reticulum. During my residency I developed an interest in protein folding in neurodegenerative disorders. Whereas many neurologic illnesses are caused by mutations that result in mis-folding and accumulation of specific proteins, DYT-1 dystonia may result from an altered enzyme involved in protein folding. I believe that elucidating the function of disease genes is best accomplished by combined biochemical and genetic approaches. I hope to further my scientific training in both the field of protein folding and more particularly in genetics so that I can expand the scope of our investigations.
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