The most common cause of early onset dystonia is DYT1 dystonia. DYT1 dystonia is inherited in an autosomal dominant manner with 30-40% penetrance. The DYT1 mutation is a GAG deletion near the carboxy terminus of the protein, torsin A. At this time, the function of torsin A is unknown. The lack of phenotypic expression in 60% to70% of individuals with the DYT1 mutation indicates that secondary factors (environmental or genetic) must operate in conjunction with the DYT1 mutation to result in a dystonic phenotype. To determine the role of the DYT1 mutation in generating a dystonic phenotype, transgenic mice expressing either wild-type or mutant torsin A will be systemically examined for motor abnormalities. The mice will also be subject to dopamine blockade, to investigate the role of environmental stress in the generation of a dystonic phenotype. To determine if basal ganglia expression of the DYT1 mutation is sufficient for development of a dystonic phenotype, mice will undergo intrastriatal injection with a viral vector expressing either wild-type or mutant torsin A. The injected mice will be examined for changes in phenotype as well as for changes in dopaminergic transmission via HPLC.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08NS044272-05
Application #
7196417
Study Section
NST-2 Subcommittee (NST)
Program Officer
Tagle, Danilo A
Project Start
2003-05-01
Project End
2009-02-28
Budget Start
2007-03-01
Budget End
2009-02-28
Support Year
5
Fiscal Year
2007
Total Cost
$170,586
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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Sciamanna, Giuseppe; Bonsi, Paola; Tassone, Annalisa et al. (2009) Impaired striatal D2 receptor function leads to enhanced GABA transmission in a mouse model of DYT1 dystonia. Neurobiol Dis 34:133-45
Pisani, A; Martella, G; Tscherter, A et al. (2006) Altered responses to dopaminergic D2 receptor activation and N-type calcium currents in striatal cholinergic interneurons in a mouse model of DYT1 dystonia. Neurobiol Dis 24:318-25
Sharma, Nutan; Baxter, Mark G; Petravicz, Jeremy et al. (2005) Impaired motor learning in mice expressing torsinA with the DYT1 dystonia mutation. J Neurosci 25:5351-5