Transcriptional phenotype in a novel ataxin-3 knock-in mouse model for spinocerebellar ataxia type 3

Spinocerebellar ataxia type 3 is the most common autosomal dominant inherited ataxia worldwide and caused by a CAG repeat expansion in the Ataxin-3 gene resulting in a polyQ expansion in the corresponding protein. The disease is characterized by neuropathological (aggregate formation, cell loss), phenotypical (gait instability, body weight reduction) and transcriptional changes. So far there is no mouse model available representing all the different aspects of the disease, but a representative model is highly needed to gain a better understanding of the disease pathomechanism. Here we characterized a novel Ataxin-3 knock-in mouse model, expressing an expansion of 304 CAG/CAAs either heterozygous or homozygous in the murine Ataxin-3 locus using biochemical, behavioral and transcriptomic approaches. Further, we correlated the transcriptional changes of the knock-in mice to those found in human SCA3 patients, to prove the comparability of our model. The novel Ataxin-3 knock-in mouse is characterized by the expression of polyQ-expanded Ataxin-3 in the murine protein, leading to massive aggregate formation, especially in brain regions known to be vulnerable in SCA3 patients, and impairment of Purkinje cells. Caused by these neuropathological changes, the mice demonstrated phenotypically reduction in body weight accompanied by gait and balance instability. Transcriptomic analysis of cerebellar tissue revealed downregulation of differentially expressed genes enriched in myelinating oligodendrocytes. Comparing these transcriptional changes with those found in cerebellar tissue of SCA3 patients, we discovered an overlap of differentially expressed genes pointing towards disturbances in the myelin sheaths and myelinating oligodendrocytes. gene expression of cerebellar samples was analyzed in samples of 2 and 12 month old mice. For each time point 5 wild-type and 5 knock-in mice, carrying the CAG expansion in the ataxin-3 locus were analyzed