Generation of Mouse Models for Early Onset Dystonia

Massachusetts General Hospital, Boston MA

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Abstract

Early onset torsin dystonia is a movement disorder inherited in an autosomal dominant manner with reduced penetrance (30-40%). Most cases of the disease are caused by a 3 base pair deletion in the DYT1 (TOR1A) gene however we have recently described a family with an 18 base pair deletion in this same gene. The mechanism(s) underlying dystonia remain elusive however the defect(s) is thought to involve the basal ganglia with evidence from multiple forms of dystonia as well as more recent data from this PO1 implicating alterations in dopaminergic metabolism in the pathogenesis of dystonia. With the discovery of the DYT1 gene, we can now generate mouse models specific to this disorder to explore the mechanism of disease. In the previous cycle, we have created transgenic (tg) animals that overexpress either the wild-type (wt) or GAG deletion (delta E) mutation under the control of a strong promoter (CMV). Preliminary results suggest that these mice have a defect in motor learning as tested on the rotorod. In addition, we have produced tetracycline inducible bigenic mice that express either the wt or GAG deletion specifically in neurons that are being assessed. In this application, we will use these models and generate additional genetically modified animals to determine the normal function of the DYT1 gene product and whether the disease is caused by a gain or loss of function. In addition, we will address whether the dopaminergic system is involved in DYT1 dystonia by selectively knocking-ont or over-expressing the DYT1 gene in dopaminergic neurons. All mice generated in this Project will be evaluated for neurologic and motoric phenotypes and undergo neurochemical and neuropathological analyses during development (Project 2) and adulthood (Project 1). The mice will also be available for testing genetic modifiers discovered in Project 3. The generation of these mice should lead to clues about the function of this gene (DYT1) and eventually to viable therapies for this disease.