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Human Molecular Genetics Advance Access originally published online on August 20, 2008
Human Molecular Genetics 2008 17(22):3601-3616; doi:10.1093/hmg/ddn255
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Protective role of Engrailed in a Drosophila model of Huntington's disease

Bruno Mugat1, Marie-Laure Parmentier2, Nathalie Bonneaud1, Ho Yin Edwin Chan3 and Florence Maschat1,*

1 Institute of Human Genetics, UPR1142, CNRS, 141, rue de la Cardonille, 34396 Montpellier Cedex 05, France 2 Institut de Génomique Fonctionnelle, UMR 5203 CNRS, U661 INSERM, Université Montpellier 1, 2. 141, rue de la Cardonille, 34094 Montpellier Cedex 05, France 3 Laboratory of Drosophila Research, Department of Biochemistry, Faculty of Science, The Chinese University of Hong Kong, Shatin N.T, Hong Kong, China

* To whom correspondence should be addressed. Tel: +33 499619956; Fax: +33 499619957;Email: fmaschat{at}igh.cnrs.fr

Received June 18, 2008; Accepted August 19, 2008

Huntington's disease (HD) is caused by the expansion of the polyglutamine (polyQ) tract in the human Huntingtin (hHtt) protein (polyQ-hHtt). Although this mutation behaves dominantly, htt loss of function may also contribute to HD pathogenesis. Using a Drosophila model of HD, we found that Engrailed (EN), a transcriptional activator of endogenous Drosophila htt (dhtt), is able to prevent aggregation of polyQ-hHtt. To interpret these findings, we tested and identified a protective role of N-terminal fragments of both Drosophila and Human wild-type Htt onto polyQ-hHtt-induced cellular defects. In addition, N-terminal parts of normal hHtt were also able to rescue eye degeneration due to the loss of Drosophila endogenous dhtt function. Thus, our data indicate that Drosophila and Human Htt share biological properties, and confirm a model whereby EN activates endogenous dhtt, which in turn prevents polyQ-hHtt-induced phenotypes. The protective role of wild-type hHtt N-terminal parts, specifically onto polyQ-hHtt-induced cellular toxicity suggests that the HD may be considered as a dominant negative disease rather than solely dominant.


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