Cargando…
A role for cerebellum in the hereditary dystonia DYT1
DYT1 is a debilitating movement disorder caused by loss-of-function mutations in torsinA. How these mutations cause dystonia remains unknown. Mouse models which have embryonically targeted torsinA have failed to recapitulate the dystonia seen in patients, possibly due to differential developmental c...
Autores principales: | , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2017
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5340526/ https://www.ncbi.nlm.nih.gov/pubmed/28198698 http://dx.doi.org/10.7554/eLife.22775 |
_version_ | 1782512845827604480 |
---|---|
author | Fremont, Rachel Tewari, Ambika Angueyra, Chantal Khodakhah, Kamran |
author_facet | Fremont, Rachel Tewari, Ambika Angueyra, Chantal Khodakhah, Kamran |
author_sort | Fremont, Rachel |
collection | PubMed |
description | DYT1 is a debilitating movement disorder caused by loss-of-function mutations in torsinA. How these mutations cause dystonia remains unknown. Mouse models which have embryonically targeted torsinA have failed to recapitulate the dystonia seen in patients, possibly due to differential developmental compensation between rodents and humans. To address this issue, torsinA was acutely knocked down in select brain regions of adult mice using shRNAs. TorsinA knockdown in the cerebellum, but not in the basal ganglia, was sufficient to induce dystonia. In agreement with a potential developmental compensation for loss of torsinA in rodents, torsinA knockdown in the immature cerebellum failed to produce dystonia. Abnormal motor symptoms in knockdown animals were associated with irregular cerebellar output caused by changes in the intrinsic activity of both Purkinje cells and neurons of the deep cerebellar nuclei. These data identify the cerebellum as the main site of dysfunction in DYT1, and offer new therapeutic targets. DOI: http://dx.doi.org/10.7554/eLife.22775.001 |
format | Online Article Text |
id | pubmed-5340526 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-53405262017-03-10 A role for cerebellum in the hereditary dystonia DYT1 Fremont, Rachel Tewari, Ambika Angueyra, Chantal Khodakhah, Kamran eLife Neuroscience DYT1 is a debilitating movement disorder caused by loss-of-function mutations in torsinA. How these mutations cause dystonia remains unknown. Mouse models which have embryonically targeted torsinA have failed to recapitulate the dystonia seen in patients, possibly due to differential developmental compensation between rodents and humans. To address this issue, torsinA was acutely knocked down in select brain regions of adult mice using shRNAs. TorsinA knockdown in the cerebellum, but not in the basal ganglia, was sufficient to induce dystonia. In agreement with a potential developmental compensation for loss of torsinA in rodents, torsinA knockdown in the immature cerebellum failed to produce dystonia. Abnormal motor symptoms in knockdown animals were associated with irregular cerebellar output caused by changes in the intrinsic activity of both Purkinje cells and neurons of the deep cerebellar nuclei. These data identify the cerebellum as the main site of dysfunction in DYT1, and offer new therapeutic targets. DOI: http://dx.doi.org/10.7554/eLife.22775.001 eLife Sciences Publications, Ltd 2017-02-15 /pmc/articles/PMC5340526/ /pubmed/28198698 http://dx.doi.org/10.7554/eLife.22775 Text en © 2017, Fremont et al http://creativecommons.org/licenses/by/4.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Neuroscience Fremont, Rachel Tewari, Ambika Angueyra, Chantal Khodakhah, Kamran A role for cerebellum in the hereditary dystonia DYT1 |
title | A role for cerebellum in the hereditary dystonia DYT1 |
title_full | A role for cerebellum in the hereditary dystonia DYT1 |
title_fullStr | A role for cerebellum in the hereditary dystonia DYT1 |
title_full_unstemmed | A role for cerebellum in the hereditary dystonia DYT1 |
title_short | A role for cerebellum in the hereditary dystonia DYT1 |
title_sort | role for cerebellum in the hereditary dystonia dyt1 |
topic | Neuroscience |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5340526/ https://www.ncbi.nlm.nih.gov/pubmed/28198698 http://dx.doi.org/10.7554/eLife.22775 |
work_keys_str_mv | AT fremontrachel aroleforcerebelluminthehereditarydystoniadyt1 AT tewariambika aroleforcerebelluminthehereditarydystoniadyt1 AT angueyrachantal aroleforcerebelluminthehereditarydystoniadyt1 AT khodakhahkamran aroleforcerebelluminthehereditarydystoniadyt1 AT fremontrachel roleforcerebelluminthehereditarydystoniadyt1 AT tewariambika roleforcerebelluminthehereditarydystoniadyt1 AT angueyrachantal roleforcerebelluminthehereditarydystoniadyt1 AT khodakhahkamran roleforcerebelluminthehereditarydystoniadyt1 |