Modeling spinocerebellar ataxia type 7 in the mouse

Abstract

AbstractAutosomal dominant spinocerebellar ataxia 7 (SCA7) is associated with cone‐rod dystrophy. The causative gene codes for ATAXIN‐7, a ubiquitous protein part of the transcriptional complex SAGA. The coding region contains a CAG triplet repeat translated into a poly‐glutamine (Q) stretch. While there are 4 to 36 repeats per allele in the healthy population, higher numbers are found in SCA7 patients. Longer expansions are typically associated with early onset and cause visual loss before cerebellar ataxia. The SCA7 retinal degeneration has previously been modeled using an overexpression of 90‐repeats ATAXIN‐7 only in rods using the rhodopsin promoter (Rho‐90Q) or a knock‐in with 266 repeats in the mouse Ataxin‐7 gene (KI‐266Q). Rho‐90Q may not be a good model for a cone‐rod dystrophy due to the promoter used. KI‐266Q showed reduction of both photopic and scotopic ERG, but the early and severe phenotype compromises animal fertility and causes death at 4‐5 months, thus offering limited possibilities to test therapeutic approaches, especially in the pre‐symptomatic phase. We have thus characterized the retinal phenotype of KI‐140Q mice, in which mouse Ataxin‐7 includes a shorter (140) polyQ stretch. While the photopic ERG and cone opsins expression is comparable in the mutant and control mice at 5 weeks, they progressively decrease and are extinct around 20–25 weeks in KI‐140Q. The retinal structure is preserved at 9 weeks, followed by a moderate thinning of the segments and outer nuclear layer. Overall, the KI‐140Q recapitulates the symptoms of the cone‐rod dystrophy found in patients, and offer a reasonable time‐window to assess treatment efficacy in both the pre‐symptomatic and symptomatic phases of the disease.