TY - JOUR TI - TorsinB overexpression prevents abnormal twisting in DYT1 dystonia mouse models AU - Li, Jay AU - Liang, Chun-Chi AU - Pappas, Samuel S AU - Dauer, William T A2 - Orr, Harry T A2 - Wassum, Kate M A2 - Gonzalez-Alegre, Pedro VL - 9 PY - 2020 DA - 2020/03/23 SP - e54285 C1 - eLife 2020;9:e54285 DO - 10.7554/eLife.54285 UR - https://doi.org/10.7554/eLife.54285 AB - 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. KW - dystonia KW - mouse model KW - genetic redundancy KW - movement disorder KW - basal ganglia KW - cholinergic interneuron JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -