A novel Ataxin-3 knock-in mouse model mimics the human SCA3 disease phenotype including neuropathological, behavioral, and transcriptional abnormalities

Background Spinocerebellar ataxia type 3 is the most common autosomal dominant inherited ataxia worldwide and is 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 specific transcriptional changes in affected brain regions. So far, there is no mouse model available representing all the different aspects of the disease, yet highly needed to gain a better understanding of the disease pathomechanism. Methods Here, we characterized a novel Ataxin-3 knock-in mouse model, expressing either a heterozygous or homozygous expansion of 304 CAG/CAAs in the murine Ataxin-3 locus using biochemical, behavioral, and transcriptomic approaches. Further, we compared the transcriptional changes of the knock-in mice to those found in human SCA3 patients, to evaluate the comparability of our model. Results The novel Ataxin-3 knock-in mouse is characterized by the expression of a polyQ-expansion in the murine Ataxin-3 protein, leading to massive aggregate formation, especially in brain regions known to be vulnerable in SCA3 patients, and impairment of Purkinje cells. Along these neuropathological changes, mice showed a reduction in body weight accompanied by gait and balance instability. Transcriptomic analysis of cerebellar tissue revealed age-dependent differential expression, enriched for genes attributed to 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 similar gene expression perturbances in several genes linked to myelin sheaths and myelinating oligodendrocytes. Conclusion The novel Ataxin-3 knock-in model shares neuropathological, behavioral, and transcriptomic features with human SCA3 patients and, therefore, represents an ideal model to investigate early-onset developments, therapy studies, or longitudinal biomarker alterations.