A Conditional Pan-NeuronalDrosophilaModel of Spinocerebellar Ataxia 7 with a Reversible Adult Phenotype Suitable for Identifying Modifier Genes (original) (raw)

2007, The Journal of Neuroscience

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 conditionalDrosophilamodel 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 gene...

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