DYT12 is a rapid-onset dystonia with parkinsonism (RDP). DYT12 patients have both generalized dystonia and parkinsonian symptoms. Generally patients exhibit no symptoms until precipitated by a mild to severe stressor (e.g. strenuous exercise, traumatic brain injury). Symptoms develop within minutes to days post- stressor and are permanent. In DYT12 the first attack is common in late adolescence or early adulthood. The inheritance of DYT12 dystonia has been determined to be autosomal dominant. The causative gene is ATP1A3, which encodes the 13 subunit of the Na?ATPase (13), which is only expressed in neurons. While the genetics of ATP1A3 causing DYT12 dystonia has been successfully elucidated, the role of its mutated forms in causing DYT12 dystonia is unknown. Furthermore, neural circuits or synaptic connections affected in the patients are not identified. Finally, there is no effective therapeutics for DYT12 since there is no way to determine the extent of symptoms prior to the stressor. These unknowns hamper efforts to adequately understand the pathophysiology of DYT12 dystonia, thus preventing the development of effective therapeutic strategies for patients. The broad, long-term objective of our research is to use transgenic mice to determine: 1) the functional role of 13 protein in vivo, and 2) how the loss of function of 13 leads to DYT12 dystonia. The objective of this application is to characterize Atp1a3 mutant mice to answer these questions. We hypothesize that we will be able to distinguish from behaviorally penetrant and non-penetrant Atp1a3 mutant mice using a novel voluntary wheel running paradigm. We further hypothesize that behaviorally penetrant mutant mice will have neural circuitry dysfunction especially in the basal ganglia, dopaminergic modulation, and in the cortex and striatum may have altered synaptic transmission and plasticity, ultimately affecting motor control and posture. The rationale for the proposed research is that once the roles of Atp1a3 in causing dysfunction of movement control in the brain are determined, possible interventions to correct DYT12 can be developed. We plan to test our hypothesis with the following Specific Aims: (1) To test the hypothesis that stress induces behaviorally penetrant mutant mice as defined as decreased activity in voluntary wheel running. a. We will differentially examine stressed animals versus non-stressed animals in voluntary wheel running. b. Stressed behaviorally non-penetrant mice will undergo another repetitive stressor and retested to see if they become behaviorally penetrant. (2) To test the hypothesis that the behaviorally penetrant versus non-penetrant mutant mice will differentially exhibit disrupted dopaminergic function, we will measure levels of tissue dopamine and its metabolites by HPLC, striatal dopamine receptors by radioligand binding assays and western blot analysis, dopamine transporter activity, and dopamine system function via animals'response to pharmacological administration of dopaminergic agonists and antagonists in the open field apparatus, (3) To test the hypothesis that the behaviorally penetrant versus non-penetrant mutant mice will differentially exhibit disrupted motor control, balance, and sensory perception, we will test mice in open field apparatus, beam-walking, rotarod for motor coordination and balance, pole test mainly for striatum-specific motor deficits, tail flick and von Frey for sensory tests. The successful completion of the above Specific Aims will help us to determine the function of Atp1a3 in vivo and how the mutant form of Atp1a3 causes DYT12 dystonia. The results should significantly increase our understanding of the pathophysiology of DYT12 dystonia, which will ultimately aid the development of therapeutic treatments for DYT12 dystonia patients.

Public Health Relevance

Dystonia affects more than half of a million people in US alone. The project is aimed at developing and analyzing a genetic mouse model of DYT12 dystonia to understand how malfunction of a protein, 13 subunit of the Na?ATPase, could lead to this debilitating disorder. The results from the proposed research should significantly increase the understanding of the pathophysiology of DYT12 dystonia, which can ultimately aid the development of therapeutic treatments for DYT12 dystonia patients and other dystonia patients.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
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Tagle, Danilo A
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University of Florida
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Allen, Richard P; Donelson, Nathan C; Jones, Byron C et al. (2017) Animal models of RLS phenotypes. Sleep Med 31:23-28
DeAndrade, Mark P; Trongnetrpunya, Amy; Yokoi, Fumiaki et al. (2016) Electromyographic evidence in support of a knock-in mouse model of DYT1 Dystonia. Mov Disord 31:1633-1639
Yokoi, Fumiaki; Dang, Mai T; Liu, Jun et al. (2015) Decreased dopamine receptor 1 activity and impaired motor-skill transfer in Dyt1 ?GAG heterozygous knock-in mice. Behav Brain Res 279:202-10
Yokoi, Fumiaki; Chen, Huan-Xin; Dang, Mai Tu et al. (2015) Behavioral and electrophysiological characterization of Dyt1 heterozygous knockout mice. PLoS One 10:e0120916
Oleas, Janneth; Yokoi, Fumiaki; DeAndrade, Mark P et al. (2013) Engineering animal models of dystonia. Mov Disord 28:990-1000
Yokoi, Fumiaki; Cheetham, Chad C; Campbell, Susan L et al. (2013) Pre-synaptic release deficits in a DYT1 dystonia mouse model. PLoS One 8:e72491
Sciamanna, Giuseppe; Hollis, Robert; Ball, Chelsea et al. (2012) Cholinergic dysregulation produced by selective inactivation of the dystonia-associated protein torsinA. Neurobiol Dis 47:416-27
Zhang, Lin; Yokoi, Fumiaki; Parsons, Dee S et al. (2012) Alteration of striatal dopaminergic neurotransmission in a mouse model of DYT11 myoclonus-dystonia. PLoS One 7:e33669
DeAndrade, Mark P; Johnson Jr, Russell L; Unger, Erica L et al. (2012) Motor restlessness, sleep disturbances, thermal sensory alterations and elevated serum iron levels in Btbd9 mutant mice. Hum Mol Genet 21:3984-92
DeAndrade, Mark P; Zhang, Li; Doroodchi, Atbin et al. (2012) Enhanced hippocampal long-term potentiation and fear memory in Btbd9 mutant mice. PLoS One 7:e35518

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