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)
Type
Research Project (R01)
Project #
3R01NS058949-04S1
Application #
8838340
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Sieber, Beth-Anne
Project Start
Project End
Budget Start
Budget End
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
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
Cook, Jared F; Hill, Deborah F; Snively, Beverly M et al. (2014) Cognitive impairment in rapid-onset dystonia-parkinsonism. Mov Disord 29:344-50
Barbano, Richard L; Hill, Deborah F; Snively, Beverly M et al. (2012) New triggers and non-motor findings in a family with rapid-onset dystonia-parkinsonism. Parkinsonism Relat Disord 18:737-41
Calderon, D Paola; Fremont, Rachel; Kraenzlin, Franca et al. (2011) The neural substrates of rapid-onset Dystonia-Parkinsonism. Nat Neurosci 14:357-65
Anselm, I A; Sweadner, K J; Gollamudi, S et al. (2009) Rapid-onset dystonia-parkinsonism in a child with a novel atp1a3 gene mutation. Neurology 73:400-1