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Downregulation of glutamic acid decarboxylase in Drosophila TDP-43-null brains provokes paralysis by affecting the organization of the neuromuscular synapses

Amyotrophic lateral sclerosis is a progressive neurodegenerative disease that affects the motor system, comprised of motoneurons and associated glia. Accordingly, neuronal or glial defects in TDP-43 function provoke paralysis due to the degeneration of the neuromuscular synapses in Drosophila. To id...

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Autores principales: Romano, Giulia, Holodkov, Nikola, Klima, Raffaella, Grilli, Federica, Guarnaccia, Corrado, Nizzardo, Monica, Rizzo, Federica, Garcia, Rodolfo, Feiguin, Fabian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5789004/
https://www.ncbi.nlm.nih.gov/pubmed/29379112
http://dx.doi.org/10.1038/s41598-018-19802-3
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author Romano, Giulia
Holodkov, Nikola
Klima, Raffaella
Grilli, Federica
Guarnaccia, Corrado
Nizzardo, Monica
Rizzo, Federica
Garcia, Rodolfo
Feiguin, Fabian
author_facet Romano, Giulia
Holodkov, Nikola
Klima, Raffaella
Grilli, Federica
Guarnaccia, Corrado
Nizzardo, Monica
Rizzo, Federica
Garcia, Rodolfo
Feiguin, Fabian
author_sort Romano, Giulia
collection PubMed
description Amyotrophic lateral sclerosis is a progressive neurodegenerative disease that affects the motor system, comprised of motoneurons and associated glia. Accordingly, neuronal or glial defects in TDP-43 function provoke paralysis due to the degeneration of the neuromuscular synapses in Drosophila. To identify the responsible molecules and mechanisms, we performed a genome wide proteomic analysis to determine differences in protein expression between wild-type and TDP-43-minus fly heads. The data established that mutant insects presented reduced levels of the enzyme glutamic acid decarboxylase (Gad1) and increased concentrations of extracellular glutamate. Genetic rescue of Gad1 activity in neurons or glia was sufficient to recuperate flies locomotion, synaptic organization and glutamate levels. Analogous recovery was obtained by treating TDP-43-null flies with glutamate receptor antagonists demonstrating that Gad1 promotes synapses formation and prevents excitotoxicity. Similar suppression of TDP-43 provoked the downregulation of GAD67, the Gad1 homolog protein in human neuroblastoma cell lines and analogous modifications were observed in iPSC-derived motoneurons from patients carrying mutations in TDP-43, uncovering conserved pathological mechanisms behind the disease.
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spelling pubmed-57890042018-02-08 Downregulation of glutamic acid decarboxylase in Drosophila TDP-43-null brains provokes paralysis by affecting the organization of the neuromuscular synapses Romano, Giulia Holodkov, Nikola Klima, Raffaella Grilli, Federica Guarnaccia, Corrado Nizzardo, Monica Rizzo, Federica Garcia, Rodolfo Feiguin, Fabian Sci Rep Article Amyotrophic lateral sclerosis is a progressive neurodegenerative disease that affects the motor system, comprised of motoneurons and associated glia. Accordingly, neuronal or glial defects in TDP-43 function provoke paralysis due to the degeneration of the neuromuscular synapses in Drosophila. To identify the responsible molecules and mechanisms, we performed a genome wide proteomic analysis to determine differences in protein expression between wild-type and TDP-43-minus fly heads. The data established that mutant insects presented reduced levels of the enzyme glutamic acid decarboxylase (Gad1) and increased concentrations of extracellular glutamate. Genetic rescue of Gad1 activity in neurons or glia was sufficient to recuperate flies locomotion, synaptic organization and glutamate levels. Analogous recovery was obtained by treating TDP-43-null flies with glutamate receptor antagonists demonstrating that Gad1 promotes synapses formation and prevents excitotoxicity. Similar suppression of TDP-43 provoked the downregulation of GAD67, the Gad1 homolog protein in human neuroblastoma cell lines and analogous modifications were observed in iPSC-derived motoneurons from patients carrying mutations in TDP-43, uncovering conserved pathological mechanisms behind the disease. Nature Publishing Group UK 2018-01-29 /pmc/articles/PMC5789004/ /pubmed/29379112 http://dx.doi.org/10.1038/s41598-018-19802-3 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
Romano, Giulia
Holodkov, Nikola
Klima, Raffaella
Grilli, Federica
Guarnaccia, Corrado
Nizzardo, Monica
Rizzo, Federica
Garcia, Rodolfo
Feiguin, Fabian
Downregulation of glutamic acid decarboxylase in Drosophila TDP-43-null brains provokes paralysis by affecting the organization of the neuromuscular synapses
title Downregulation of glutamic acid decarboxylase in Drosophila TDP-43-null brains provokes paralysis by affecting the organization of the neuromuscular synapses
title_full Downregulation of glutamic acid decarboxylase in Drosophila TDP-43-null brains provokes paralysis by affecting the organization of the neuromuscular synapses
title_fullStr Downregulation of glutamic acid decarboxylase in Drosophila TDP-43-null brains provokes paralysis by affecting the organization of the neuromuscular synapses
title_full_unstemmed Downregulation of glutamic acid decarboxylase in Drosophila TDP-43-null brains provokes paralysis by affecting the organization of the neuromuscular synapses
title_short Downregulation of glutamic acid decarboxylase in Drosophila TDP-43-null brains provokes paralysis by affecting the organization of the neuromuscular synapses
title_sort downregulation of glutamic acid decarboxylase in drosophila tdp-43-null brains provokes paralysis by affecting the organization of the neuromuscular synapses
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5789004/
https://www.ncbi.nlm.nih.gov/pubmed/29379112
http://dx.doi.org/10.1038/s41598-018-19802-3
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