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Human Molecular Genetics Advance Access published online on November 17, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddi012
© 2004 by Oxford University Press
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Article

A transgenic mouse model of early-onset DYT1 dystonia

P. Shashidharan 1*, D. Sandu 2, U. Potla 2, I. A. Armata 2, R. H. Walker 3, K. S. McNaught 2, D. Weisz 4, T. Sreenath 5, M. F. Brin 6, and C. W. Olanow 2

1 Department of Neurology, Box 1137, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029
2 Department of Neurology, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029
3 Department of Neurology, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029; Veterans Affairs, Bronx, NY
4 Department of Neurosurgery, Mount Sinai School of Medicine, MD
5 Functional Genomics unit/NIDCR Bldg. 30, Bethesda, MD
6 Allergan Inc, Irvine, California

* To whom correspondence should be addressed.
P. Shashidharan, E-mail: pullani.shashi{at}mssm.edu


  Abstract

Early-onset dystonia is an autosomal dominant movement disorder associated with deletion of a glutamic acid residue in torsinA. We generated four independent lines of transgenic mice by overexpressing human {Delta}E-torsinA using a neuron specific enolase promoter. The transgenic mice developed abnormal involuntary movements with dystonic-appearing, self-clasping of limbs, as early as 3 weeks after birth. Animals also showed hyperkinesia, and rapid bi-directional circling. Approximately 40% of transgenic mice from each line demonstrated these severe behavioral abnormalities. Neurochemical analyses revealed decreases in striatal dopamine in affected transgenic mice while levels were increased in those that had no behavioral changes. Immunohistochemistry demonstrated perinuclear inclusions and aggregates that stained positively for ubiquitin, torsinA, and lamin, a marker of the nuclear envelope. Inclusions were detected in neurons of the pedunculopontine nucleus and in other brain stem regions in a pattern similar to what has been described in DYT1 patients. This transgenic mouse model demonstrates behavioral and pathologic features similar to patients with early-onset dystonia and may help to better understand the pathophysiology of this disorder and to develop more effective therapies.


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