A cell autonomous torsinA requirement for cholinergic neuron survival and motor control
- University of Michigan, United States
- Columbia University, United States
Abstract
Cholinergic dysfunction is strongly implicated in dystonia pathophysiology. Previously (Pappas et al., eLife 2015;4:e08352), we reported that Dlx5/6-Cre mediated forebrain deletion of the DYT1 dystonia protein torsinA (Dlx-CKO) causes abnormal twisting and selective degeneration of dorsal striatal cholinergic interneurons (ChI) (1). A central question raised by that work is whether the ChI loss is cell autonomous or requires torsinA loss from neurons synaptically connected to ChIs. Here, we addressed this question by using ChAT-Cre mice to conditionally delete torsinA from cholinergic neurons ('ChAT-CKO'). ChAT-CKO mice phenocopy the Dlx-CKO phenotype of selective dorsal striatal ChI loss and identify an essential requirement for torsinA in brainstem and spinal cholinergic neurons. ChAT-CKO mice are tremulous, weak, and exhibit trunk twisting and postural abnormalities. These findings are the first to demonstrate a cell autonomous requirement for torsinA in specific populations of cholinergic neurons, strengthening the connection between torsinA, cholinergic dysfunction and dystonia pathophysiology.
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All data generated during this study are included in the manuscript and supporting files
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Author details
Funding
National Institute of Neurological Disorders and Stroke (RO1NS077730)
- William T Dauer
Tyler's Hope for a Dystonia Cure
- William T Dauer
National Institutes of Health (RO1NS057482)
- Umrao R Monani
National Institutes of Health (R21NS099921)
- Umrao R Monani
National Institutes of Health (R56NS104218)
- Umrao R Monani
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 experiments were performed according to the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All procedures involving animals were approved by the University of Michigan Institutional Animal Care and Use Committee (animal use protocol PRO00006600). All effort was taken to minimize the number of animals used and to prevent discomfort or distress.
Copyright
© 2018, Pappas 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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A cell autonomous torsinA requirement for cholinergic neuron survival and motor control
eLife 7:e36691.
https://doi.org/10.7554/eLife.36691
