title: A conditional pan-neuronal Drosophila model of spinocerebellar ataxia 7 with a reversible adult phenotype suitable for identifying modifier genes.
abstract: 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.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité 679, Paris F-75013, France.
authors.forename: Morwena
authors.initials: M
authors.lastname: Latouche
authors.forename: Christelle
authors.initials: C
authors.lastname: Lasbleiz
authors.forename: Elodie
authors.initials: E
authors.lastname: Martin
authors.forename: Véronique
authors.initials: V
authors.lastname: Monnier
authors.forename: Thomas
authors.initials: T
authors.lastname: Debeir
authors.forename: Annick
authors.initials: A
authors.lastname: Mouatt-Prigent
authors.forename: Marie-Paule
authors.initials: MP
authors.lastname: Muriel
authors.forename: Lydie
authors.initials: L
authors.lastname: Morel
authors.forename: Merle
authors.initials: M
authors.lastname: Ruberg
authors.forename: Alexis
authors.initials: A
authors.lastname: Brice
authors.forename: Giovanni
authors.initials: G
authors.lastname: Stevanin
authors.forename: Hérvé
authors.initials: H
authors.lastname: Tricoire
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D000067719:Ataxin-7; D016923:Cell Death; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004330:Drosophila; D020820:Dyskinesias / Q000235:genetics; D005973:Glutamine; D006801:Humans; D045586:Intranuclear Inclusion Bodies / Q000648:ultrastructure; D008136:Longevity; D008297:Male; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D010455:Peptides / Q000235:genetics; D010641:Phenotype; D051381:Rats; D020754:Spinocerebellar Ataxias / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D013912:Threonine
chemical_list: C000593829:ATXN7 protein, human; D000067719:Ataxin-7; C000593832:Atxn7 protein, rat; D009419:Nerve Tissue Proteins; D010455:Peptides; D005973:Glutamine; C097188:polyglutamine; D013912:Threonine