Journal Article

Protective role of Engrailed in a <i>Drosophila</i> model of Huntington's disease

Bruno Mugat, Marie-Laure Parmentier, Nathalie Bonneaud, Ho Yin Edwin Chan and Florence Maschat

in Human Molecular Genetics

Volume 17, issue 22, pages 3601-3616
Published in print November 2008 | ISSN: 0964-6906
Published online August 2008 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddn255
Protective role of Engrailed in a Drosophila model of Huntington's disease

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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.

Journal Article.  8876 words.  Illustrated.

Subjects: Genetics and Genomics

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