Résumé
All spinocerebellar ataxia type 7 (SCA7) mice models that are generated, express full-length ataxin-7 with a polyglutamine (polyQ) expansion, ranging from 90 to 266 repeats and faithfully reproduces several key neurological features reported in SCA7 patients. These models have unraveled some of the early molecular events involved in SCA7 pathogenesis. Expansion of the polyQ tract in ataxin-7 markedly reduces the turnover of the mutant protein, thus increasing mutant ataxin-7 levels in neurons and presumably inducing its aggregation in the nucleus. Nuclear accumulation of mutant ataxin-7 parallels the onset of functional deficits in affected neurons, indicating that mutant ataxin-7 compromises essential nuclear functions. In the retina, from these mice, expression of genes essential for photoreceptor normal function is early and dramatically repressed, thereby triggering a progressive decline of photoreceptor activity leading to a complete loss of electrophysiological responses and eventually limited cell loss. The retinal phenotype in SCA7 mice thus results primarily from a severe and long-lasting neuronal dysfunction. These SCA7 retinal models are particularly attractive to further explore the therapeutic potential of drugs that could improve the transcriptional changes observed in polyQ disorders. Comparison of different polyQ mouse models reveals that either very long CAG repeats or significant over expression of transgenes with modest repeat lengths are required to generate a phenotype during the short lifespan of the mouse. Both models are thus valuable tools to further dissect the molecular mechanisms underlying SCA7 pathogenesis.