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The Journal of Neuroscience, March 7, 2007, 27(10):2483-2492; doi:10.1523/JNEUROSCI.5453-06.2007

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Neurobiology of Disease
A Conditional Pan-Neuronal Drosophila Model of Spinocerebellar Ataxia 7 with a Reversible Adult Phenotype Suitable for Identifying Modifier Genes

Morwena Latouche,^1,2 * Christelle Lasbleiz,^3 * Elodie Martin,^1,2 Véronique Monnier,³ Thomas Debeir,^1,2 Annick Mouatt-Prigent,^1,2 Marie-Paule Muriel,^1,2 Lydie Morel,¹ Merle Ruberg,^1,2 Alexis Brice,^1,2,4 Giovanni Stevanin,^1,2,4 and Hérvé Tricoire³

¹Institut National de la Santé et de la Recherche Médicale, Unité 679, Paris F-75013, France, ²Université Pierre and Marie Curie–Paris 6, Institut Fédératif de Recherche de Neurosciences (IFR70), Unité Mixte de Recherche (UMR) S679, Group Hospitalier Pitié-Salpêtriére, Paris F-75013, France, ³Centre National de la Rechereche Scientifique, UMR 7592, Insititut Jacques Monod, Campus Universitaire de Jussieu, Paris F-75251, France, and ⁴Assistance Publique–Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière, Départment de Génétique, Cytogénétique, et Embryologie, Paris F-75013, France

Correspondence should be addressed to Giovanni Stevanin, Institut National de la Santé et de la Recherche Médicale, Unité 679, Groupe Pitié-Salpêtrière, 47 Boulevard de l'Hôpital, 75013 Paris, France. Email: stevanin{at}ccr.jussieu.fr

Spinocerebellar ataxia 7 (SCA7) is a neurodegenerative disease caused by a polyglutamine (polyQ) expansion in the ataxin 7 (ATXN7) protein, a member of a multiprotein complex involved in histone acetylation. We have created a conditional Drosophila model of SCA7 in which expression of truncated ATXN7 (ATXN7T) with a pathogenic polyQ expansion is induced in neurons in adult flies. In this model, mutant ATXN7T accumulated in neuronal intranuclear inclusions containing ubiquitin, the 19S proteasome subunit, and HSP70 (heat shock protein 70), as in patients. Aggregation was accompanied by a decrease in locomotion and lifespan but limited neuronal death. Disaggregation of the inclusions, when expression of expanded ATXN7T was stopped, correlated with improved locomotor function and increased lifespan, suggesting that the pathology may respond to treatment. Lifespan was then used as a quantitative marker in a candidate gene approach to validate the interest of the model and to identify generic modulators of polyQ toxicity and specific modifiers of SCA7. Several molecular pathways identified in this focused screen (proteasome function, unfolded protein stress, caspase-dependent apoptosis, and histone acetylation) were further studied in primary neuronal cultures. Sodium butyrate, a histone deacetylase inhibitor, improved the survival time of the neurons. This model is therefore a powerful tool for studying SCA7 and for the development of potential therapies for polyQ diseases.

Key words: spinocerebellar ataxia 7; Drosophila; neurodegenerative disease; inducible expression; ataxin 7; polyglutamine; neurodegeneration; ataxias; trinucleotide repeat diseases

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Received Aug. 16, 2006; revised Jan. 25, 2007; accepted Jan. 27, 2007.

Correspondence should be addressed to Giovanni Stevanin, Institut National de la Santé et de la Recherche Médicale, Unité 679, Groupe Pitié-Salpêtrière, 47 Boulevard de l'Hôpital, 75013 Paris, France. Email: stevanin{at}ccr.jussieu.fr

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