Forebrain deletion of the dystonia protein torsinA causes dystonic-like movements and loss of striatal cholinergic neurons
Striatal dysfunction plays an important role in dystonia, but the striatal cell types that contribute to abnormal movements are poorly defined. We demonstrate that conditional deletion of the DYT1 dystonia protein torsinA in embryonic progenitors of forebrain cholinergic and GABAergic neurons causes...
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eLife Sciences Publications Ltd
2015-06-01
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| Online Access: | https://elifesciences.org/articles/08352 |
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doaj-9d4d4dc0369b4370b4eceffea8ccb2882021-05-04T23:50:52ZengeLife Sciences Publications LtdeLife2050-084X2015-06-01410.7554/eLife.08352Forebrain deletion of the dystonia protein torsinA causes dystonic-like movements and loss of striatal cholinergic neuronsSamuel S Pappas0Katherine Darr1Sandra M Holley2Carlos Cepeda3Omar S Mabrouk4Jenny-Marie T Wong5Tessa M LeWitt6Reema Paudel7Henry Houlden8Robert T Kennedy9Michael S Levine10William T Dauer11Department of Neurology, University of Michigan, Ann Arbor, United StatesDepartment of Neurology, University of Michigan, Ann Arbor, United StatesIntellectual and Developmental Disabilities Research Center, Brain Research Institute, Semel Institute for Neuroscience, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United StatesIntellectual and Developmental Disabilities Research Center, Brain Research Institute, Semel Institute for Neuroscience, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United StatesDepartment of Pharmacology, University of Michigan, Ann Arbor, United StatesDepartment of Chemistry, University of Michigan, Ann Arbor, United StatesDepartment of Neurology, University of Michigan, Ann Arbor, United StatesDepartment of Molecular Neuroscience, Institute of Neurology, University College London, London, United KingdomDepartment of Molecular Neuroscience, Institute of Neurology, University College London, London, United KingdomDepartment of Chemistry, University of Michigan, Ann Arbor, United StatesIntellectual and Developmental Disabilities Research Center, Brain Research Institute, Semel Institute for Neuroscience, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United StatesDepartment of Neurology, University of Michigan, Ann Arbor, United States; Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, United StatesStriatal dysfunction plays an important role in dystonia, but the striatal cell types that contribute to abnormal movements are poorly defined. We demonstrate that conditional deletion of the DYT1 dystonia protein torsinA in embryonic progenitors of forebrain cholinergic and GABAergic neurons causes dystonic-like twisting movements that emerge during juvenile CNS maturation. The onset of these movements coincides with selective degeneration of dorsal striatal large cholinergic interneurons (LCI), and surviving LCI exhibit morphological, electrophysiological, and connectivity abnormalities. Consistent with the importance of this LCI pathology, murine dystonic-like movements are reduced significantly with an antimuscarinic agent used clinically, and we identify cholinergic abnormalities in postmortem striatal tissue from DYT1 dystonia patients. These findings demonstrate that dorsal LCI have a unique requirement for torsinA function during striatal maturation, and link abnormalities of these cells to dystonic-like movements in an overtly symptomatic animal model.https://elifesciences.org/articles/08352dystoniatorsinAcholinergic interneuronstriatumneurodegenerationneurogenetics |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Samuel S Pappas Katherine Darr Sandra M Holley Carlos Cepeda Omar S Mabrouk Jenny-Marie T Wong Tessa M LeWitt Reema Paudel Henry Houlden Robert T Kennedy Michael S Levine William T Dauer |
| spellingShingle |
Samuel S Pappas Katherine Darr Sandra M Holley Carlos Cepeda Omar S Mabrouk Jenny-Marie T Wong Tessa M LeWitt Reema Paudel Henry Houlden Robert T Kennedy Michael S Levine William T Dauer Forebrain deletion of the dystonia protein torsinA causes dystonic-like movements and loss of striatal cholinergic neurons eLife dystonia torsinA cholinergic interneuron striatum neurodegeneration neurogenetics |
| author_facet |
Samuel S Pappas Katherine Darr Sandra M Holley Carlos Cepeda Omar S Mabrouk Jenny-Marie T Wong Tessa M LeWitt Reema Paudel Henry Houlden Robert T Kennedy Michael S Levine William T Dauer |
| author_sort |
Samuel S Pappas |
| title |
Forebrain deletion of the dystonia protein torsinA causes dystonic-like movements and loss of striatal cholinergic neurons |
| title_short |
Forebrain deletion of the dystonia protein torsinA causes dystonic-like movements and loss of striatal cholinergic neurons |
| title_full |
Forebrain deletion of the dystonia protein torsinA causes dystonic-like movements and loss of striatal cholinergic neurons |
| title_fullStr |
Forebrain deletion of the dystonia protein torsinA causes dystonic-like movements and loss of striatal cholinergic neurons |
| title_full_unstemmed |
Forebrain deletion of the dystonia protein torsinA causes dystonic-like movements and loss of striatal cholinergic neurons |
| title_sort |
forebrain deletion of the dystonia protein torsina causes dystonic-like movements and loss of striatal cholinergic neurons |
| publisher |
eLife Sciences Publications Ltd |
| series |
eLife |
| issn |
2050-084X |
| publishDate |
2015-06-01 |
| description |
Striatal dysfunction plays an important role in dystonia, but the striatal cell types that contribute to abnormal movements are poorly defined. We demonstrate that conditional deletion of the DYT1 dystonia protein torsinA in embryonic progenitors of forebrain cholinergic and GABAergic neurons causes dystonic-like twisting movements that emerge during juvenile CNS maturation. The onset of these movements coincides with selective degeneration of dorsal striatal large cholinergic interneurons (LCI), and surviving LCI exhibit morphological, electrophysiological, and connectivity abnormalities. Consistent with the importance of this LCI pathology, murine dystonic-like movements are reduced significantly with an antimuscarinic agent used clinically, and we identify cholinergic abnormalities in postmortem striatal tissue from DYT1 dystonia patients. These findings demonstrate that dorsal LCI have a unique requirement for torsinA function during striatal maturation, and link abnormalities of these cells to dystonic-like movements in an overtly symptomatic animal model. |
| topic |
dystonia torsinA cholinergic interneuron striatum neurodegeneration neurogenetics |
| url |
https://elifesciences.org/articles/08352 |
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