Pathobiology of GNAL-Associated Dystonia

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Dystonia has recently been redefined as a “movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both.” Dystonia is also a clinical sign that can be the presenting or prominent manifestation of many neurodegenerative and neurometabolic disorders. Etiological categories include isolated dystonia, secondary dystonia, heredodegenerative diseases with dystonia, and dystonia plus. Many cases of isolated dystonia are believed to be genetic in origin and mutations in GNAL may be the most prevalent known genetic cause of mainly adult- onset isolated dystonia. GNAL encodes Gα(olf) [major isoform] and XLGα(olf) [long isoform] which are both expressed in human striatum and cerebellum. The overall goals of our proposal are to use Gα(olf)/XLGα(olf) deficiency as a bridge to understand the cellular pathobiology of isolated dystonia, and employ conditional knock-out (cKO) mouse models to explore the neural circuitry that drives isolated dystonia. These goals will be achieved through three specific aims. First, we will determine the CNS localization of the major and long Gnal isoforms with cell-type specificity. Second, we will characterize the temporal changes in epigenetic marks (DNA methylation, histone modifications) and gene expression associated with Gα(olf)/XLGα(olf) deficiency in indirect pathway medium spiny neurons (iMSNs), direct pathway MSNs (dMSNs), and Purkinje cells (PCs). Third, we will determine the behavioral effects of Gnal cKO in iMSNs and PCs. Completion of these aims will radically expand upon our current understanding of isolated and tardive dystonia pathogenesis and Gα(olf)/XLGα(olf) signaling pathways.