Department of Medical Genetics, University of Tuebingen, Tuebingen, Germany.
Hum Mol Genet. 2009 Nov 15;18(22):4282-95. doi: 10.1093/hmg/ddp381. Epub 2009 Aug 10.
Spinocerebellar ataxia type 3 (SCA3) is caused by the expansion of a CAG repeat tract that affects the MJD1 gene which encodes the ataxin-3 protein. In order to analyze whether symptoms caused by ataxin-3 with an expanded repeat are reversible in vivo, we generated a conditional mouse model of SCA3 using the Tet-Off system. We used a full-length human ataxin-3 cDNA with 77 repeats in order to generate the responder mouse line. After crossbreeding with a PrP promoter mouse line, double transgenic mice developed a progressive neurological phenotype characterized by neuronal dysfunction in the cerebellum, reduced anxiety, hyperactivity, impaired Rotarod performance and lower body weight gain. When ataxin-3 expression was turned off in symptomatic mice in an early disease state, the transgenic mice were indistinguishable from negative controls after 5 months of treatment. These results show that reducing the production of pathogenic ataxin-3 indeed may be a promising approach to treat SCA3, provided that such treatment is applied before irreversible damage has taken place and that it is continued for a sufficiently long time.
脊髓小脑共济失调 3 型（SCA3）是由 CAG 重复序列的扩展引起的，该重复序列影响编码共济失调蛋白-3 的 MJD1 基因。为了分析体内由扩展重复引起的共济失调蛋白-3 引起的症状是否可逆，我们使用 Tet-Off 系统生成了 SCA3 的条件性小鼠模型。我们使用全长人类共济失调蛋白-3 cDNA 与 77 个重复，以生成应答者小鼠系。与 PrP 启动子小鼠系杂交后，双转基因小鼠表现出进行性神经表型，特征为小脑神经元功能障碍、焦虑减轻、过度活跃、转棒试验表现受损和体重增加减少。当在疾病早期的症状性小鼠中关闭共济失调蛋白-3 的表达时，在经过 5 个月的治疗后，转基因小鼠与阴性对照没有区别。这些结果表明，减少致病性共济失调蛋白-3 的产生确实可能是治疗 SCA3 的一种有前途的方法，前提是这种治疗在不可逆损伤发生之前进行，并且持续足够长的时间。
