Generation of a mouse model of L-DOPA-responsive dystonia (DRD)

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DESCRIPTION (provided by applicant): Dystonia is the third most common movement disorder, after essential tremor and Parkinson disease, with a prevalence of ~330 per million. Dystonia is broadly characterized by simultaneous and sometimes sustained contractions of agonist and antagonist muscles. These co-contractions result in twisting movements and postures that have a wide range of speed, amplitude and rhythmicity that varies among patients. The general goal of our research is to understand the pathophysiology of dystonia. Unlike Parkinson disease or Huntington disease where neurodegeneration provides clues to the pathogenesis of the movement disorder, idiopathic dystonia is a functional movement disorder without obvious markers or cell death to help define pathophysiology. Despite a strong clinico-pathological correlation between the basal ganglia and dystonia, there is little understanding of the underlying neuronal dysfunction. Moreover, the few animal models of dystonia associated with basal ganglia function are of limited value because the pathophysiology is inconsistent with abnormalities in human dystonias. Our approach to this problem is to model a monogenic dystonic disorder to provide broad insight into pathophysiological mechanisms. We have identified L-DOPA responsive dystonia (DRD), as a leading candidate for modeling dystonia associated with basal ganglia dysfunction. DRD is caused by mutations in genes encoding either GTP cyclohydrolase or tyrosine hydroxylase (TH) and is characterized by early onset generalized dystonia that is ameliorated after administration of low doses of L-DOPA, the metabolic precursor of dopamine. DRD caused by mutations in TH is particularly amenable for modeling because there is already a wealth of basic information on which to build, including an enormous body of work describing normal TH function and dopaminergic regulation of motor control. Therefore, we will develop and characterize a knockin mouse bearing a human mutation in TH that is associated with DRD. Therefore, we will develop and characterize a knockin mouse bearing an EA2 mutation. The specific aims of this proposal are 1) to develop and characterize a knockin mouse model of DRD. 2) To behaviorally characterize the DRD knockin mice. Development and characterization of an animal model exhibiting basal ganglia dysfunction that is mechanistically faithful and reliably reproducible is critical to understanding pathophysiology in dystonia and essential for developing novel therapeutics. Dystonia is the third most common movement disorder with a prevalence of ~330 per million. Dystonia is broadly characterized by simultaneous and sometimes sustained contractions of agonist and antagonist muscles. There is little understanding of the pathophysiological mechanisms underlying dystonia. Therefore, we will develop and characterize a knockin mouse bearing a human mutation that causes L-DOPA-responsive dystonia to provide insight into general pathomechanisms underlying dystonia.