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I(NaP) selective inhibition reverts precocious inter- and motorneurons hyperexcitability in the Sod1-G93R zebrafish ALS model

The pathogenic role of SOD1 mutations in amyotrophic lateral sclerosis (ALS) was investigated using a zebrafish disease model stably expressing the ALS-linked G93R mutation. In addition to the main pathological features of ALS shown by adult fish, we found remarkably precocious alterations in the de...

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Autores principales: Benedetti, Lorena, Ghilardi, Anna, Rottoli, Elsa, De Maglie, Marcella, Prosperi, Laura, Perego, Carla, Baruscotti, Mirko, Bucchi, Annalisa, Del Giacco, Luca, Francolini, Maura
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4832213/
https://www.ncbi.nlm.nih.gov/pubmed/27079797
http://dx.doi.org/10.1038/srep24515
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author Benedetti, Lorena
Ghilardi, Anna
Rottoli, Elsa
De Maglie, Marcella
Prosperi, Laura
Perego, Carla
Baruscotti, Mirko
Bucchi, Annalisa
Del Giacco, Luca
Francolini, Maura
author_facet Benedetti, Lorena
Ghilardi, Anna
Rottoli, Elsa
De Maglie, Marcella
Prosperi, Laura
Perego, Carla
Baruscotti, Mirko
Bucchi, Annalisa
Del Giacco, Luca
Francolini, Maura
author_sort Benedetti, Lorena
collection PubMed
description The pathogenic role of SOD1 mutations in amyotrophic lateral sclerosis (ALS) was investigated using a zebrafish disease model stably expressing the ALS-linked G93R mutation. In addition to the main pathological features of ALS shown by adult fish, we found remarkably precocious alterations in the development of motor nerve circuitry and embryo behavior, and suggest that these alterations are prompted by interneuron and motor neuron hyperexcitability triggered by anomalies in the persistent pacemaker sodium current I(NaP). The riluzole-induced modulation of I(NaP) reduced spinal neuron excitability, reverted the behavioral phenotypes and improved the deficits in motor nerve circuitry development, thus shedding new light on the use of riluzole in the management of ALS. Our findings provide a valid phenotype-based tool for unbiased in vivo drug screening that can be used to develop new therapies.
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spelling pubmed-48322132016-04-20 I(NaP) selective inhibition reverts precocious inter- and motorneurons hyperexcitability in the Sod1-G93R zebrafish ALS model Benedetti, Lorena Ghilardi, Anna Rottoli, Elsa De Maglie, Marcella Prosperi, Laura Perego, Carla Baruscotti, Mirko Bucchi, Annalisa Del Giacco, Luca Francolini, Maura Sci Rep Article The pathogenic role of SOD1 mutations in amyotrophic lateral sclerosis (ALS) was investigated using a zebrafish disease model stably expressing the ALS-linked G93R mutation. In addition to the main pathological features of ALS shown by adult fish, we found remarkably precocious alterations in the development of motor nerve circuitry and embryo behavior, and suggest that these alterations are prompted by interneuron and motor neuron hyperexcitability triggered by anomalies in the persistent pacemaker sodium current I(NaP). The riluzole-induced modulation of I(NaP) reduced spinal neuron excitability, reverted the behavioral phenotypes and improved the deficits in motor nerve circuitry development, thus shedding new light on the use of riluzole in the management of ALS. Our findings provide a valid phenotype-based tool for unbiased in vivo drug screening that can be used to develop new therapies. Nature Publishing Group 2016-04-15 /pmc/articles/PMC4832213/ /pubmed/27079797 http://dx.doi.org/10.1038/srep24515 Text en Copyright © 2016, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Benedetti, Lorena
Ghilardi, Anna
Rottoli, Elsa
De Maglie, Marcella
Prosperi, Laura
Perego, Carla
Baruscotti, Mirko
Bucchi, Annalisa
Del Giacco, Luca
Francolini, Maura
I(NaP) selective inhibition reverts precocious inter- and motorneurons hyperexcitability in the Sod1-G93R zebrafish ALS model
title I(NaP) selective inhibition reverts precocious inter- and motorneurons hyperexcitability in the Sod1-G93R zebrafish ALS model
title_full I(NaP) selective inhibition reverts precocious inter- and motorneurons hyperexcitability in the Sod1-G93R zebrafish ALS model
title_fullStr I(NaP) selective inhibition reverts precocious inter- and motorneurons hyperexcitability in the Sod1-G93R zebrafish ALS model
title_full_unstemmed I(NaP) selective inhibition reverts precocious inter- and motorneurons hyperexcitability in the Sod1-G93R zebrafish ALS model
title_short I(NaP) selective inhibition reverts precocious inter- and motorneurons hyperexcitability in the Sod1-G93R zebrafish ALS model
title_sort i(nap) selective inhibition reverts precocious inter- and motorneurons hyperexcitability in the sod1-g93r zebrafish als model
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4832213/
https://www.ncbi.nlm.nih.gov/pubmed/27079797
http://dx.doi.org/10.1038/srep24515
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