A conditional pan-neuronal Drosophila model of spinocerebellar ataxia 7 with a reversible adult phenotype suitable for identifying modifier genes.
Journal of Neuroscience. 2007-03-07; 27(10): 2483-2492
DOI: 10.1523/JNEUROSCI.5453-06.2007
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1. J Neurosci. 2007 Mar 7;27(10):2483-92.
A conditional pan-neuronal Drosophila model of spinocerebellar ataxia 7 with a
reversible adult phenotype suitable for identifying modifier genes.
Latouche M(1), Lasbleiz C, Martin E, Monnier V, Debeir T, Mouatt-Prigent A,
Muriel MP, Morel L, Ruberg M, Brice A, Stevanin G, Tricoire H.
Author information:
(1)Institut National de la Santé et de la Recherche Médicale, Unité 679, Paris
F-75013, France.
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.
DOI: 10.1523/JNEUROSCI.5453-06.2007
PMCID: PMC6672519
PMID: 17344386 [Indexed for MEDLINE]