Les différents modèles déjà établis, bien qu’essentiels à la compréhension de la pathologie, ne permettent pas un criblage facile et rapide des voies d’intérêt thérapeutique. Nous avons donc généré un modèle Drosophile de l’ataxie SCA7, exprimant de façon inductible une forme tronquée d’ataxine 7, normale ou mutante, dans tous les neurones du système nerveux afin de disséquer les mécanismes pathogènes de SCA7 de façon simple et systématique et d’identifier des gènes modulateurs du phénotype dans une visée thérapeutique. Drosophila melanogaster est en effet un outil très puissant qui présente de nombreux avantages. En effet, environ 75% des loci liés à une pathologie chez l’homme ont au moins un homologue chez la Drosophile avec un très fort degré de conservation de la fonction des gènes (Cauchi and van den Heuvel, 2006). Le cerveau de Drosophile est aussi un atout pour la modélisation de maladies neurodégénératives. Il compte environ 300,000 neurones qui sont organisés, comme pour les mammifères en zones de fonctions spécifiques, par exemple, la mémoire, l’olfaction, la vision. D’autre part, l’existence d’une très grande collection de mutants permet la réalisation de cribles génétiques afin d’appréhender les mécanismes physiopathologiques mis en place. De plus, il s’agit d’un organisme facile d’entretien, qui possède un cycle de vie assez court. Il est également possible, et de manière très simple grâce au système UAS/GAL4, de cibler l’expression du transgène d’intérêt de façon tissu spécifique dans l’œil, les muscles, les neurones ou de façon ubiquitaire. Ainsi, la Drosophile s’est avérée être un très bon modèle pour l’étude des maladies neurodégénératives en général (Muqit and Feany, 2002; Zoghbi and Botas, 2002) et pour les maladies à polyQ en particulier (Jackson et al., 1998; Warrick et al., 1998). En collaboration avec l’équipe d’Hervé Tricoire (CNRS UMR7592, Institut Jacques Monod,), nous avons donc généré un modèle drosophile SCA7 et comparé les voies pathogéniques identifiées dans les modèles déjà existants avec les voies impliquées dans notre modèle SCA7. Cette démarche nous a permis de confirmer certains mécanismes généraux de la neurotoxicité des protéines à polyQ mais aussi de mettre en évidence des mécanismes spécifiques de SCA7. L’originalité de notre modèle a consisté à utiliser un système inductible permettant le ciblage au système nerveux adulte uniquement afin de s’affranchir des problèmes développementaux propres à la Drosophile, et surtout nous permettant de tester la réversibilité du phénotype par arrêt de l’expression du transgène. II. Etude d’une voie d’intérêt thérapeutique médiée par un interacteur de l’ataxine 7 : la protéine PML Malgré l’expression ubiquitaire de l’ataxine 7, la dégénérescence ciblée de certaines structures suggère que des interactions spécifiques ont lieu dans ces structures. Ainsi, il a été montré que la protéine CAP (Cbl-associated protein) était recrutée dans les agrégats d’Atxn7 et jouerait un rôle dans l’ubiquitylation de la protéine pathologique, et donc dans sa dégradation (Lebre et al., 2001). D’autre part, la protéine PML (promyelocytic leukemia protein) colocalise avec une partie des inclusions dans les cerveaux de patients atteints de maladies à polyglutamines, dont SCA7 (Takahashi et al., 2003; Takahashi et al., 2002). PML contient un domaine RING présent chez les enzymes E3 ubiquitine ligase, suggérant que PML puisse jouer un rôle dans l’ubiquitylation de protéines intranucléaires (Freemont, 2000; Jensen et al., 2001; Shiels et al., 2001). 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