TorsinB overexpression prevents abnormal twisting in DYT1 dystonia mouse models
- University of Michigan, United States
- University of Texas Southwestern, United States
Abstract
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.
Data availability
Our study did not generate sequencing or structural data. All source data files have been provided.
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Author details
Funding
Bachmann-Strauss Dystonia and Parkinson Foundation
- William T Dauer
National Institutes of Health (R01 NS077730)
- William T Dauer
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All procedures complied with national ethical guidelines regarding the use of rodents in scientific research and were approved by the University of Michigan (Protocol #00006600 and Protocol #00008870) and University of Texas Southwestern (Protocol #102767) Institutional Animal Care and Use Committees. Every effort was made to minimize both number of mice utilized as well as suffering.
Copyright
© 2020, Li et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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TorsinB overexpression prevents abnormal twisting in DYT1 dystonia mouse models
eLife 9:e54285.
https://doi.org/10.7554/eLife.54285
