(Overall Abstract) Dystonia is the third most common movement disorder with most cases having a hereditary predisposition. Our overall goal is to elucidate the molecular, cellular and neuronal circuitry defects in hereditary forms of early onset dystonia and to find common pathways in their etiology and potential targeted drugs for therapeutic intervention. Members of our team discovered three genes underlying early onset dystonia, TOR1A (DYT1), THAP1 (DYT6) and GNAL (DYT25) and have developed and characterized mouse and Drosophila models of DYT1 dystonia, as well as initiating studies on mouse models of DYT6 and DYT25 dystonia. We hypothesize that the core pathophysiology lies in abnormal neurotransmitter signaling, primarily in the striatum, which manifests throughout life as abnormal synaptic plasticity. Studies will analyze neuronal cultures, as well as neurophysiology in these dystonia mouse models, as well as enhancer/suppressor genes in Drosophila mutants. Common themes include cholinergic and dopaminergic neurotransmitter interactions in the striatum, transcriptional and functional control of signaling proteins, and transport of mRNAs in ribonucleoprotein particles (RNPs) for translation at synapses. We will approach these themes with an armamentarium of research tools, including state-of-the-art human molecular genetics, primary neuronal and iPS cell-derived neuronal cultures, and Drosophila and mouse models of dystonia examined using genetic and cell biologic methods and electrophysiologic analysis of slice explants and microdialysis in mouse models. This highly integrated P01 will be led by Dr. Xandra Breakefield, Director and Laurie Ozelius, Co-Director and includes: Project 1 - Genes and susceptibility factors in primary torsion dystonia (PI Dr. Laurie Ozelius, Mt. Sinai Sch. Med.); Project 2 - TorsinA as a key link in receptor-mediated signaling (PI Dr. Xandra Breakefield, Co-Is Drs. D. Cristopher Bragg and Naoto Ito, Mass. Gen. Hosp.); Project 3 - Cholinergic and dopaminergic mechanisms in mouse models of dystonia (Dr. David Standaert, Univ. Ala. Birmingham); Core A - Administration; and Core B - Clinical Core (Dr. Nutan Sharma, Mass. Gen. Hosp.). Clinical information and samples feed directly into Projects 1, 2 and 3. These studies will elucidate common molecular pathways involved in human dystonia to inform therapeutic advances.
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