A cell autonomous torsinA requirement for cholinergic neuron survival and motor control
Cholinergic dysfunction is strongly implicated in dystonia pathophysiology. Previously (Pappas et al., 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 choline...
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doaj-cf7b8c67ff654c7ab18479b5cd989cf62021-05-05T16:06:15ZengeLife Sciences Publications LtdeLife2050-084X2018-08-01710.7554/eLife.36691A cell autonomous torsinA requirement for cholinergic neuron survival and motor controlSamuel S Pappas0https://orcid.org/0000-0002-6980-2058Jay Li1https://orcid.org/0000-0002-8146-4450Tessa M LeWitt2Jeong-Ki Kim3https://orcid.org/0000-0003-0218-1215Umrao R Monani4William T Dauer5https://orcid.org/0000-0003-1775-7504Department of Neurology, University of Michigan, Ann Arbor, United StatesDepartment of Neurology, University of Michigan, Ann Arbor, United States; Cell and Molecular Biology Program, University of Michigan, Ann Arbor, United StatesDepartment of Neurology, University of Michigan, Ann Arbor, United StatesDepartment of Cell Biology, Columbia University Medical Center, New York, United States; Center for Motor Neuron Biology and Disease, Columbia University Medical Center, New York, United States; Department of Pathology, Columbia University Medical Center, New York, United StatesDepartment of Cell Biology, Columbia University Medical Center, New York, United States; Center for Motor Neuron Biology and Disease, Columbia University Medical Center, New York, United States; Department of Pathology, Columbia University Medical Center, New York, United StatesDepartment of Neurology, University of Michigan, Ann Arbor, United States; Cell and Molecular Biology Program, University of Michigan, Ann Arbor, United States; Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, United StatesCholinergic dysfunction is strongly implicated in dystonia pathophysiology. Previously (Pappas et al., 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) (Pappas et al., 2015). 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.https://elifesciences.org/articles/36691dystoniacholinergicneurodegenerationDYT1torsinAmotor behavior |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Samuel S Pappas Jay Li Tessa M LeWitt Jeong-Ki Kim Umrao R Monani William T Dauer |
spellingShingle |
Samuel S Pappas Jay Li Tessa M LeWitt Jeong-Ki Kim Umrao R Monani William T Dauer A cell autonomous torsinA requirement for cholinergic neuron survival and motor control eLife dystonia cholinergic neurodegeneration DYT1 torsinA motor behavior |
author_facet |
Samuel S Pappas Jay Li Tessa M LeWitt Jeong-Ki Kim Umrao R Monani William T Dauer |
author_sort |
Samuel S Pappas |
title |
A cell autonomous torsinA requirement for cholinergic neuron survival and motor control |
title_short |
A cell autonomous torsinA requirement for cholinergic neuron survival and motor control |
title_full |
A cell autonomous torsinA requirement for cholinergic neuron survival and motor control |
title_fullStr |
A cell autonomous torsinA requirement for cholinergic neuron survival and motor control |
title_full_unstemmed |
A cell autonomous torsinA requirement for cholinergic neuron survival and motor control |
title_sort |
cell autonomous torsina requirement for cholinergic neuron survival and motor control |
publisher |
eLife Sciences Publications Ltd |
series |
eLife |
issn |
2050-084X |
publishDate |
2018-08-01 |
description |
Cholinergic dysfunction is strongly implicated in dystonia pathophysiology. Previously (Pappas et al., 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) (Pappas et al., 2015). 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. |
topic |
dystonia cholinergic neurodegeneration DYT1 torsinA motor behavior |
url |
https://elifesciences.org/articles/36691 |
work_keys_str_mv |
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