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Human Molecular Genetics Advance Access originally published online on January 10, 2006
Human Molecular Genetics 2006 15(4):607-623; doi:10.1093/hmg/ddi477
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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 and Scott O. Zeitlin*

Department of Neuroscience, University of Virginia School of Medicine, PO Box 801392, Charlottesville, VA 22908-1392, USA

* To whom correspondence should be addressed at: Department of Neuroscience, University of Virginia School of Medicine, 409 Lane Road, MR4, Room 5022, Charlottesville, VA 22908-1392, USA. Tel: +1 4349245011; Fax: +1 4349824380; Email: soz4n{at}virginia.edu

Received November 8, 2005; Accepted January 4, 2006

Huntingtin (htt), the protein encoded by the Huntington's disease (HD) gene, contains a polymorphic stretch of glutamines (polyQ) near its N-terminus. When the polyQ stretch is expanded beyond 37Q, HD results. However, the role of the normal polyQ stretch in the function of htt is still unknown. To determine the contribution of the polyQ stretch to normal htt 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 htt'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 whether 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 htt's polyQ stretch is required for modulating longevity in culture and support the hypothesis that the polyQ stretch may also modulate a htt function involved in regulating energy homeostasis.


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