Journal Article

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

Erin B.D. Clabough and Scott O. Zeitlin

in Human Molecular Genetics

Volume 15, issue 4, pages 607-623
Published in print February 2006 | ISSN: 0964-6906
Published online January 2006 | e-ISSN: 1460-2083 | DOI: https://dx.doi.org/10.1093/hmg/ddi477
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

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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 (HdhΔQ). Hdh(ΔQ/ΔQ) 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 HdhΔQ mice, we characterized the growth and energy status of primary embryonic and adult Hdh(ΔQ/ΔQ) fibroblasts in culture. The HdhΔQ 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.

Journal Article.  13441 words.  Illustrated.

Subjects: Genetics and Genomics

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