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A Drosophila Model of Essential Tremor
Essential Tremor (ET) is one of the most common neurological diseases, with an estimated 7 million affected individuals in the US; the pathophysiology of the disorder is poorly understood. Recently, we identified a mutation (KCNS2 (Kv9.2), c.1137 T > A, p.(D379E) in an electrically silent voltage...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5955955/ https://www.ncbi.nlm.nih.gov/pubmed/29769701 http://dx.doi.org/10.1038/s41598-018-25949-w |
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author | Smith, Philip Arias, Ronald Sonti, Shilpa Odgerel, Zagaa Santa-Maria, Ismael McCabe, Brian D. Tsaneva-Atanasova, Krasimira Louis, Elan D. Hodge, James J. L. Clark, Lorraine N. |
author_facet | Smith, Philip Arias, Ronald Sonti, Shilpa Odgerel, Zagaa Santa-Maria, Ismael McCabe, Brian D. Tsaneva-Atanasova, Krasimira Louis, Elan D. Hodge, James J. L. Clark, Lorraine N. |
author_sort | Smith, Philip |
collection | PubMed |
description | Essential Tremor (ET) is one of the most common neurological diseases, with an estimated 7 million affected individuals in the US; the pathophysiology of the disorder is poorly understood. Recently, we identified a mutation (KCNS2 (Kv9.2), c.1137 T > A, p.(D379E) in an electrically silent voltage-gated K(+) channel α-subunit, Kv9.2, in a family with ET, that modulates the activity of Kv2 channels. We have produced transgenic Drosophila lines that express either the human wild type Kv9.2 (hKv9.2) or the ET causing mutant Kv9.2 (hKv9.2-D379E) subunit in all neurons. We show that the hKv9.2 subunit modulates activity of endogenous Drosophila K(+) channel Shab. The mutant hKv9.2-D379E subunit showed significantly higher levels of Shab inactivation and a higher frequency of spontaneous firing rate consistent with neuronal hyperexcitibility. We also observed behavioral manifestations of nervous system dysfunction including effects on night time activity and sleep. This functional data further supports the pathogenicity of the KCNS2 (p.D379E) mutation, consistent with our prior observations including co-segregation with ET in a family, a likely pathogenic change in the channel pore domain and absence from population databases. The Drosophila hKv9.2 transgenic model recapitulates several features of ET and may be employed to advance our understanding of ET disease pathogenesis. |
format | Online Article Text |
id | pubmed-5955955 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-59559552018-05-21 A Drosophila Model of Essential Tremor Smith, Philip Arias, Ronald Sonti, Shilpa Odgerel, Zagaa Santa-Maria, Ismael McCabe, Brian D. Tsaneva-Atanasova, Krasimira Louis, Elan D. Hodge, James J. L. Clark, Lorraine N. Sci Rep Article Essential Tremor (ET) is one of the most common neurological diseases, with an estimated 7 million affected individuals in the US; the pathophysiology of the disorder is poorly understood. Recently, we identified a mutation (KCNS2 (Kv9.2), c.1137 T > A, p.(D379E) in an electrically silent voltage-gated K(+) channel α-subunit, Kv9.2, in a family with ET, that modulates the activity of Kv2 channels. We have produced transgenic Drosophila lines that express either the human wild type Kv9.2 (hKv9.2) or the ET causing mutant Kv9.2 (hKv9.2-D379E) subunit in all neurons. We show that the hKv9.2 subunit modulates activity of endogenous Drosophila K(+) channel Shab. The mutant hKv9.2-D379E subunit showed significantly higher levels of Shab inactivation and a higher frequency of spontaneous firing rate consistent with neuronal hyperexcitibility. We also observed behavioral manifestations of nervous system dysfunction including effects on night time activity and sleep. This functional data further supports the pathogenicity of the KCNS2 (p.D379E) mutation, consistent with our prior observations including co-segregation with ET in a family, a likely pathogenic change in the channel pore domain and absence from population databases. The Drosophila hKv9.2 transgenic model recapitulates several features of ET and may be employed to advance our understanding of ET disease pathogenesis. Nature Publishing Group UK 2018-05-16 /pmc/articles/PMC5955955/ /pubmed/29769701 http://dx.doi.org/10.1038/s41598-018-25949-w Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Smith, Philip Arias, Ronald Sonti, Shilpa Odgerel, Zagaa Santa-Maria, Ismael McCabe, Brian D. Tsaneva-Atanasova, Krasimira Louis, Elan D. Hodge, James J. L. Clark, Lorraine N. A Drosophila Model of Essential Tremor |
title | A Drosophila Model of Essential Tremor |
title_full | A Drosophila Model of Essential Tremor |
title_fullStr | A Drosophila Model of Essential Tremor |
title_full_unstemmed | A Drosophila Model of Essential Tremor |
title_short | A Drosophila Model of Essential Tremor |
title_sort | drosophila model of essential tremor |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5955955/ https://www.ncbi.nlm.nih.gov/pubmed/29769701 http://dx.doi.org/10.1038/s41598-018-25949-w |
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