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The Journal of Neuroscience, February 25, 2004, 24(8):1881-1887; doi:10.1523/JNEUROSCI.4407-03.2004

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Neurobiology of Disease
Disease Progression Despite Early Loss of Polyglutamine Protein Expression in SCA7 Mouse Model

Dominique Helmlinger,¹ Gretta Abou-Sleymane,¹ Gaël Yvert,¹ Stéphane Rousseau,² Chantal Weber,¹ Yvon Trottier,¹ Jean-Louis Mandel,¹ and Didier Devys¹

¹Department of Molecular Pathology, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique-Institut National de la Santé et de la Recherche Médicale-Université Louis Pasteur, and ²Mouse Clinical Institute, 67404 Illkirch, France

Nine neurodegenerative diseases including Huntington's disease (HD) and spinocerebellar ataxia type 7 (SCA7) are caused by an expansion of a polyglutamine (polyQ) stretch in the respective proteins. Aggregation of expanded polyQ-containing proteins into the nucleus is a hallmark of these diseases. Recent evidence indicates that transcriptional dysregulation may contribute to the molecular pathogenesis of these diseases. Using SCA7 and HD mouse models in which we recently described a retinal phenotype, we investigated whether altered gene expression underlies photoreceptor dysfunction. In both models, rhodopsin promoter activity was early and dramatically repressed, suggesting that downregulation of photoreceptor-specific genes plays a major role in polyQ-induced retinal dysfunction. Because the rhodopsin promoter drives mutant ataxin-7 expression in our SCA7 mice, we also assessed whether downregulation of mutant SCA7 transgene would reverse retinopathy progression and aggregate formation. Although residual expression of mutant ataxin-7 was found negligible from 9 weeks of age, SCA7 transgenic mice showed a progressive decline of photoreceptor activity leading to a complete loss of electroretinographic responses from 1 year of age. At this age, aggregates were cleared in only half of the photoreceptors, indicating that their formation is not fully reversible in this model. We demonstrate here that abolishing full-length mutant ataxin-7 expression did not reverse retinopathy progression in SCA7 mice, raising the possibility that some polyQ-induced pathological events might be irreversible.

Key words: neurodegeneration; polyglutamine; retina; transcriptional alteration; reversibility; aggregates

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Received Sep 29, 2003; revised November 20, 2003; accepted December 19, 2003.

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