Rapid-onset dystonia-parkinsonism (RDP) is an autosomal dominant disease with abrupt onset of dystonia and parkinsonism over days to weeks followed by little improvement. In 2004, we reported that RDP is caused by mutations in the a3 subunit of the Na,K ATPase, the ATP1A3 gene. In 2007 we published data on 10 families. In many of the 20 known RDP families permanent dystonia presents acutely after stress, fever, or alcohol excess. The clinical presentation correlates with known properties of the a3 subunit. The Na,K-ATPase converts metabolic energy by restoring the Na+, K+ electrochemical gradient and as a result impacts neuronal activity;reuptake of glutamate and other transmitters. The premise of this proposal is that RDP provides a window into the role of the ATP1A3 gene in brain dysfunction with the potential to impact the diagnosis and management of primary dystonia. We hypothesize that similar to other genetic dystonias, carriers of the ATP1A3 mutations will have a spectrum of neurologic and psychologic symptoms and that ATP1A3 plays a role in more common dystonias. A multidisciplinary team of investigators with expertise in dystonia (Drs. Brashear and Ozelius) and biochemistry and cell biology of Na,K-ATPase (Dr. Sweadner) has been assembled to answer three essential questions in RDP: (1) what is the full phenotypic spectrum of ATP1A3 mutations, including motor and non-motor, (2) what is the mutational spectrum in RDP and what role does the ATP1A3 gene have as a susceptibility factor in dystonias with characteristics similar to RDP, and (3) what occurs at the cellular level in stressed neurons using our heterozygote ATP1A3 knockout mouse as a model system? To answer these questions we will i] clearly define the full clinical phenotype of RDP in the families using detailed neurologic, psychiatric and learning assessments;ii] determine if ATP1A3 mutations are involved in the more common dystonias that share some of the RDP characteristics (laryngeal, oromandibular, musician's dystonia), and iii] determine the effect of physiologic stress on the neurons in our existing heterozygote mouse. The proposed interdisciplinary collaboration across institutions, of world experts of clinical, genetic, biochemical and neurobiological study of dystonia and Na,K-ATPase, will deepen both our clinical and basic understanding of this disabling disease. The results will provide a model for understanding the impact of Na,K-ATPase in neurogenetic disorders. Rapid-Onset Dystonia-Parkinsonism (RDP) has elements of both dystonia and Parkinson's, two neurologic diseases with motor and neuropsychological symptoms that hinder the quality of life of millions. RDP results from mutations in the a3 subunit of Na K-ATPase (ATP1A3) and provides a window into the affect the ATP1A3 mutations in the brain. By defining the role of the ATP1A3 gene mutations in humans and our mouse model, we will impact the study of other neurological diseases, including those with dystonic, neuropsychological, and psychiatric symptoms.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
3R01NS058949-04S1
Application #
8838340
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Sieber, Beth-Anne
Project Start
2008-04-15
Project End
2015-03-31
Budget Start
2011-04-01
Budget End
2015-03-31
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Neurology
Type
Schools of Medicine
DUNS #
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
Sweadner, Kathleen J (2016) Colorimetric Assays of Na,K-ATPase. Methods Mol Biol 1377:89-104
Arystarkhova, Elena; Sweadner, Kathleen J (2016) Functional Studies of Na(+),K(+)-ATPase Using Transfected Cell Cultures. Methods Mol Biol 1377:321-32
Sweadner, Kathleen J; Toro, Camilo; Whitlow, Christopher T et al. (2016) ATP1A3 Mutation in Adult Rapid-Onset Ataxia. PLoS One 11:e0151429
Liu, Yi Bessie; Tewari, Ambika; Salameh, Johnny et al. (2015) A dystonia-like movement disorder with brain and spinal neuronal defects is caused by mutation of the mouse laminin β1 subunit, Lamb1. Elife 4:
Paciorkowski, Alex R; McDaniel, Sharon S; Jansen, Laura A et al. (2015) Novel mutations in ATP1A3 associated with catastrophic early life epilepsy, episodic prolonged apnea, and postnatal microcephaly. Epilepsia 56:422-30
Oblak, Adrian L; Hagen, Matthew C; Sweadner, Kathleen J et al. (2014) Rapid-onset dystonia-parkinsonism associated with the I758S mutation of the ATP1A3 gene: a neuropathologic and neuroanatomical study of four siblings. Acta Neuropathol 128:81-98
Heinzen, Erin L; Arzimanoglou, Alexis; Brashear, Allison et al. (2014) Distinct neurological disorders with ATP1A3 mutations. Lancet Neurol 13:503-14
Brashear, Allison; Ozelius, Laurie J; Sweadner, Kathleen J (2014) ATP1A3 mutations: what is the phenotype? Neurology 82:468-9
Cook, Jared F; Hill, Deborah F; Snively, Beverly M et al. (2014) Cognitive impairment in rapid-onset dystonia-parkinsonism. Mov Disord 29:344-50
Evidente, Virgilio Gerald H; Fernandez, Hubert H; LeDoux, Mark S et al. (2013) A randomized, double-blind study of repeated incobotulinumtoxinA (Xeomin(®)) in cervical dystonia. J Neural Transm (Vienna) 120:1699-707

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