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TorsinB overexpression prevents abnormal twisting in DYT1 dystonia mouse models
eLife ( IF 7.7 ) Pub Date : 2020-03-23
Jay Li, Chun-Chi Liang, Samuel S Pappas, William T Dauer

Genetic redundancy can be exploited to identify therapeutic targets for inherited disorders. We explored this possibility in DYT1 dystonia, a neurodevelopmental movement disorder caused by a loss-of-function (LOF) mutation in the TOR1A gene encoding torsinA. Prior work demonstrates that torsinA and its paralog torsinB have conserved functions at the nuclear envelope. This work established that low neuronal levels of torsinB dictate the neuronal selective phenotype of nuclear membrane budding. Here, we examined whether torsinB expression levels impact the onset or severity of abnormal movements or neuropathological features in DYT1 mouse models. We demonstrate that torsinB levels bidirectionally regulate these phenotypes. Reducing torsinB levels causes a dose-dependent worsening whereas torsinB overexpression rescues torsinA LOF-mediated abnormal movements and neurodegeneration. These findings identify torsinB as a potent modifier of torsinA LOF phenotypes and suggest that augmentation of torsinB expression may retard or prevent symptom development in DYT1 dystonia.

中文翻译:

TorsinB过表达可防止DYT1肌张力障碍小鼠模型异常扭曲

可以利用遗传冗余来鉴定遗传性疾病的治疗靶标。我们探讨了DYT1肌张力障碍的这种可能性,这是一种由TOR1A的功能丧失(LOF)突变引起的神经发育运动障碍编码torsinA的基因。先前的工作表明,torsinA及其旁系同源物torsinB在核被膜上具有保守的功能。这项工作确定了低水平的TorsinB神经元决定了核膜萌芽的神经元选择性表型。在这里,我们检查了torsinB表达水平是否影响DYT1小鼠模型中异常运动或神经病理学特征的发作或严重程度。我们证明了torsinB水平双向调节这些表型。降低torsinB水平会导致剂量依赖性恶化,而torsinB的过表达可以挽救torsinA LOF介导的异常运动和神经变性。这些发现确定了torsinB是torsinA LOF表型的有效修饰剂,并表明torsinB表达的增加可能会延迟或预防DYT1肌张力障碍的症状发展。
更新日期:2020-03-24
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