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Deregulation of ZPR1 causes respiratory failure in spinal muscular atrophy

Spinal muscular atrophy (SMA) is caused by the low levels of survival motor neuron (SMN) protein and is characterized by motor neuron degeneration and muscle atrophy. Respiratory failure causes death in SMA but the underlying molecular mechanism is unknown. The zinc finger protein ZPR1 interacts wit...

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Autores principales: Genabai, Naresh K., Kannan, Annapoorna, Ahmad, Saif, Jiang, Xiaoting, Bhatia, Kanchan, Gangwani, Laxman
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5557895/
https://www.ncbi.nlm.nih.gov/pubmed/28811488
http://dx.doi.org/10.1038/s41598-017-07603-z
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author Genabai, Naresh K.
Kannan, Annapoorna
Ahmad, Saif
Jiang, Xiaoting
Bhatia, Kanchan
Gangwani, Laxman
author_facet Genabai, Naresh K.
Kannan, Annapoorna
Ahmad, Saif
Jiang, Xiaoting
Bhatia, Kanchan
Gangwani, Laxman
author_sort Genabai, Naresh K.
collection PubMed
description Spinal muscular atrophy (SMA) is caused by the low levels of survival motor neuron (SMN) protein and is characterized by motor neuron degeneration and muscle atrophy. Respiratory failure causes death in SMA but the underlying molecular mechanism is unknown. The zinc finger protein ZPR1 interacts with SMN. ZPR1 is down regulated in SMA patients. We report that ZPR1 functions downstream of SMN to regulate HoxA5 levels in phrenic motor neurons that control respiration. Spatiotemporal inactivation of Zpr1 gene in motor neurons down-regulates HoxA5 and causes defects in the function of phrenic motor neurons that results in respiratory failure and perinatal lethality in mice. Modulation in ZPR1 levels directly correlates and influences levels of HoxA5 transcription. In SMA mice, SMN-deficiency causes down-regulation of ZPR1 and HoxA5 that result in degeneration of phrenic motor neurons. Identification of ZPR1 and HoxA5 as potential targets provides a paradigm for developing strategies to treat respiratory distress in SMA.
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spelling pubmed-55578952017-08-16 Deregulation of ZPR1 causes respiratory failure in spinal muscular atrophy Genabai, Naresh K. Kannan, Annapoorna Ahmad, Saif Jiang, Xiaoting Bhatia, Kanchan Gangwani, Laxman Sci Rep Article Spinal muscular atrophy (SMA) is caused by the low levels of survival motor neuron (SMN) protein and is characterized by motor neuron degeneration and muscle atrophy. Respiratory failure causes death in SMA but the underlying molecular mechanism is unknown. The zinc finger protein ZPR1 interacts with SMN. ZPR1 is down regulated in SMA patients. We report that ZPR1 functions downstream of SMN to regulate HoxA5 levels in phrenic motor neurons that control respiration. Spatiotemporal inactivation of Zpr1 gene in motor neurons down-regulates HoxA5 and causes defects in the function of phrenic motor neurons that results in respiratory failure and perinatal lethality in mice. Modulation in ZPR1 levels directly correlates and influences levels of HoxA5 transcription. In SMA mice, SMN-deficiency causes down-regulation of ZPR1 and HoxA5 that result in degeneration of phrenic motor neurons. Identification of ZPR1 and HoxA5 as potential targets provides a paradigm for developing strategies to treat respiratory distress in SMA. Nature Publishing Group UK 2017-08-15 /pmc/articles/PMC5557895/ /pubmed/28811488 http://dx.doi.org/10.1038/s41598-017-07603-z Text en © The Author(s) 2017 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
Genabai, Naresh K.
Kannan, Annapoorna
Ahmad, Saif
Jiang, Xiaoting
Bhatia, Kanchan
Gangwani, Laxman
Deregulation of ZPR1 causes respiratory failure in spinal muscular atrophy
title Deregulation of ZPR1 causes respiratory failure in spinal muscular atrophy
title_full Deregulation of ZPR1 causes respiratory failure in spinal muscular atrophy
title_fullStr Deregulation of ZPR1 causes respiratory failure in spinal muscular atrophy
title_full_unstemmed Deregulation of ZPR1 causes respiratory failure in spinal muscular atrophy
title_short Deregulation of ZPR1 causes respiratory failure in spinal muscular atrophy
title_sort deregulation of zpr1 causes respiratory failure in spinal muscular atrophy
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5557895/
https://www.ncbi.nlm.nih.gov/pubmed/28811488
http://dx.doi.org/10.1038/s41598-017-07603-z
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