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 Ga(olf) [major isoform] and XLGa(olf) [long isoform] which are both
expressed in human striatum and cerebellum. The overall goals of our proposal are to use Ga(olf)/XLGa(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 Ga(olf)/XLGa(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
Ga(olf)/XLGa(olf) signaling pathways.