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Human Molecular Genetics Advance Access published online on January 10, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddi477
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© The Author 2006. Published by Oxford University Press. All rights reserved
Received November 8, 2005
Revised January 4, 2006
Accepted January 4, 2006

Article

Deletion of the triplet repeat encoding polyglutamine within the mouse Huntington's disease gene results in subtle behavioral/motor phenotypes in vivo and elevated levels of ATP with cellular senescence in vitro

Erin B.D. Clabough 1 and Scott O. Zeitlin 2 *

1 Department of Neuroscience, University of Virginia School of Medicine, P.O. Box 801392, Charlottesville, VA 22908-1392, USA
2 Department of Neuroscience, University of Virginia School of Medicine, P.O. Box 801392, 409 Lane Road, MR4, Room 5022, Charlottesville, VA 22908-1392, USA

* To whom correspondence should be addressed.
Scott O. Zeitlin, E-mail: soz4n{at}virginia.edu


  Abstract

Huntingtin, the protein encoded by the Huntington's disease gene (HD), contains a polymorphic stretch of glutamines (polyQ) near its amino terminus. When the polyQ stretch is expanded beyond 37Q, Huntington's disease results. However, the role of the normal polyQ stretch in the function of huntingtin is still unknown. To determine the contribution of the polyQ stretch to normal huntingtin function, we have generated mice with a precise deletion of the short CAG triplet repeat encoding 7Q in the mouse HD gene (Hdh{Delta}Q:Hdh({Delta}Q/{Delta}Q) mice are born with normal Mendelian frequency and exhibit no gross phenotypic differences in comparison to control littermates, suggesting that the polyQ stretch is not essential for huntingtin's functions during embryonic development. Adult mice, however, commit more errors initially in the Barnes circular maze learning and memory test, and perform slightly better than wild-type controls in the accelerating rotarod test for motor coordination. To determine if these phenotypes may reflect an altered cellular physiology in the Hdh{Delta}Q mice, we characterized the growth and energy status of primary embryonic and adult Hdh({Delta}Q/{Delta}Q) fibroblasts in culture. The Hdh{Delta}Q fibroblasts exhibited elevated levels of ATP, but senesced prematurely in comparison with wild-type fibroblasts. Taken altogether, these results suggest that huntingtin's polyQ stretch is required for modulating longevity in culture, and support the hypothesis that the polyQ stretch may also modulate a huntingtin function involved in regulating energy homeostasis.


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