Dystonia is a neurological disorder characterized by involuntary twisting movements or abnormal postures that are caused by excessive activation of specific muscles or co-activation of agonist and antagonist muscle groups. Though there are many different types and causes for human dystonia, in most cases the pathogenesis is poorly understood and treatment strategies are limited. Recently, two lines of evidence have suggested that dystonia may be associated with abnormal calcium metabolism in the brain. First, + Bay K 8644 and FPL 64176, two structurally distinct and specific L-type calcium channel agonists can provoke dystonia in normal C57L/6J mice. Second, dystonia is a prominent feature of several strains of mice carrying mutations in genes encoding calcium channel proteins or related regulatory proteins. The overall goal of this proposal is to assess the pathogenesis of dystonia in mouse models of dystonia associated with abnormal calcium channel function. Our hypothesis is that aberrant calcium function in regions involved in motor control are responsible for dystonia.
Specific aim 1 addresses the neuroanatomic and neuropharmacologic basis of dystonia in a mouse model induced by administration of L-type calcium channel agonists. We will use functional mapping techniques, 2-deoxyglucose autoradiography and immediate early gene induction, to define regions of abnormal brain activity followed by regional microinjection studies to determine which of these regions is most responsible for dystonia in this model. To define the neuropharmacologic basis of dystonia in this model, we will examine the ability of several drugs selective towards specific neurotransmitter systems to modify dystonia caused by the L-type calcium channel agonists.
Aim 2 involved the use of functional mapping in strains of mice with mutations in genes encoding calcium channel proteins to define regions of abnormal brain activity that appear normal in standard histopathologic studies. We will focus on three mutants, tottering, lethargic, and leaner, that have either generalized or inducible dystonia.
In aim 3, we will develop electromyographic criteria to characterize dystonia in the pharmacologic and genetic models, and determine if they can be applied to other mouse mutants with abnormal motor behavior that is otherwise difficult to classify. Since preliminary animal work suggests that L-type calcium channel antagonists might be useful in the treatment of human dystonia, we will conduct a pilot double-blinded crossover trial of nifedipine in patients with three easily-defined subtypes of dystonia. These studies have direct relevance for advancing our understanding of the pathogenesis and treatment of dystonia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS040470-01
Application #
6193093
Study Section
Special Emphasis Panel (ZRG1-BDCN-2 (01))
Program Officer
Gwinn, Katrina
Project Start
2000-06-01
Project End
2004-05-31
Budget Start
2000-06-01
Budget End
2001-05-31
Support Year
1
Fiscal Year
2000
Total Cost
$263,914
Indirect Cost
Name
Johns Hopkins University
Department
Neurology
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Raike, Robert S; Hess, Ellen J; Jinnah, H A (2015) Dystonia and cerebellar degeneration in the leaner mouse mutant. Brain Res 1611:56-64
Yan, Ling; Hicks, Matt; Winslow, Korey et al. (2015) Secured web-based video repository for multicenter studies. Parkinsonism Relat Disord 21:366-71
Prudente, C N; Hess, E J; Jinnah, H A (2014) Dystonia as a network disorder: what is the role of the cerebellum? Neuroscience 260:23-35
Song, Chang-Hyun; Bernhard, Doug; Hess, Ellen J et al. (2014) Subtle microstructural changes of the cerebellum in a knock-in mouse model of DYT1 dystonia. Neurobiol Dis 62:372-80
Luciano, Angelo Y; Jinnah, H A; Pfeiffer, Ronald F et al. (2014) Treatment of myoclonus-dystonia syndrome with tetrabenazine. Parkinsonism Relat Disord 20:1423-6
Göttle, Martin; Prudente, Cecilia N; Fu, Rong et al. (2014) Loss of dopamine phenotype among midbrain neurons in Lesch-Nyhan disease. Ann Neurol 76:95-107
Jinnah, H A; Albanese, Alberto (2014) The New Classification System for the Dystonias: Why Was it Needed and How was it Developed? Mov Disord Clin Pract 1:280-284
Jinnah, H A; Delong, Mahlon R; Hallett, Mark (2013) The dystonias: past, present, and future. Mov Disord 28:849-50
Shaikh, Aasef G; Wong, Aaron L; Zee, David S et al. (2013) Keeping your head on target. J Neurosci 33:11281-95
Prudente, C N; Pardo, C A; Xiao, J et al. (2013) Neuropathology of cervical dystonia. Exp Neurol 241:95-104

Showing the most recent 10 out of 41 publications