SCA3 research group, Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen, Germany.
Center for Rare Diseases, University of Tuebingen, Tuebingen, Germany.
Hum Mol Genet. 2019 May 1;28(9):1463-1473. doi: 10.1093/hmg/ddy437.
Spinocerebellar ataxia type 3 (SCA3) is caused by the expansion of CAG repeats in the ATXN3 gene leading to an elongated polyglutamine tract in the ataxin-3 protein. Previously, we demonstrated that symptoms of SCA3 are reversible in the first conditional mouse model for SCA3 directing ataxin-3 predominantly to the hindbrain. Here, we report on the effects of transgenic ataxin-3 expression in forebrain regions. Employing the Tet-off CamKII-promoter mouse line and our previously published SCA3 responder line, we generated double transgenic mice (CamKII/MJD77), which develop a neurological phenotype characterized by impairment in rotarod performance, and deficits in learning new motor tasks as well as hyperactivity. Ataxin-3 and ubiquitin-positive inclusions are detected in brains of double transgenic CamKII/MJD77 mice. After turning off the expression of pathologically expanded ataxin-3, these inclusions disappear. However, the observed phenotype could not be reversed, very likely due to pronounced apoptotic cell death in the frontal brain. Our data demonstrate that cerebellar expression is not required to induce a neurological phenotype using expanded ATXN3 as well as the pronounced sensibility of forebrain neurons for toxic ataxin-3.
脊髓小脑共济失调 3 型（SCA3）是由 ATXN3 基因中的 CAG 重复扩展引起的，导致 ataxin-3 蛋白中的延长多聚谷氨酰胺链。先前，我们证明了在第一个 SCA3 的条件性小鼠模型中，SCA3 的症状是可逆的，该模型主要使 ataxin-3 定向到后脑。在这里，我们报告了在大脑前区表达转基因 ataxin-3 的效果。利用 Tet-off CamKII-启动子小鼠系和我们之前发表的 SCA3 反应性小鼠系，我们生成了双转基因小鼠（CamKII/MJD77），它们表现出神经表型，特征为旋转棒性能受损，以及学习新运动任务的缺陷和过度活跃。在双转基因 CamKII/MJD77 小鼠的大脑中检测到 ataxin-3 和泛素阳性包涵体。在病理扩展的 ataxin-3 的表达关闭后，这些包涵体消失。然而，观察到的表型无法逆转，这很可能是由于额叶脑的明显凋亡细胞死亡。我们的数据表明，使用扩展的 ATXN3 诱导神经表型并不需要小脑表达，并且前脑神经元对毒性 ataxin-3 非常敏感。
