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Human Molecular Genetics Advance Access originally published online on November 17, 2004
Human Molecular Genetics 2005 14(1):125-133; doi:10.1093/hmg/ddi012
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Human Molecular Genetics, Vol. 14, No. 1 © Oxford University Press 2005; all rights reserved

Transgenic mouse model of early-onset DYT1 dystonia

P. Shashidharan1,*, D. Sandu1, U. Potla1, I.A. Armata1, R.H. Walker1,3, K.S. McNaught1, D. Weisz2, T. Sreenath4, M.F. Brin5 and C.W. Olanow1

1Department of Neurology and 2Department of Neurosurgery, Mount Sinai School of Medicine, One Gustave L. Levy Place, NY 10029, USA, 3Veterans Affairs, Bronx, NY, USA, 4Functional Genomics unit/NIDCR Bldg 30, Bethesda, MD, USA and 5Allergan Inc, Irvine, CA, USA

* To whom correspondence should be addressed at: Department of Neurology, Box 1137, Mount Sinai School of Medicine, One Gustave L. Levy Place, NY, 10029, USA. Tel: +1 2122415807; Fax: +1 2123481310; Email: pullani.shashi{at}mssm.edu

Received October 10, 2004; Accepted November 1, 2004

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, although 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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