TDP-43 regulates GAD1 mRNA splicing and GABA signaling in Drosophila CNS

Abstract Alterations in the function of the RNA-binding protein TDP-43 are largely associated with the pathogenesis of amyotrophic lateral sclerosis (ALS), a devastating disease of the human motor system that leads to motoneurons degeneration and reduced life expectancy by molecular mechanisms not w...

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Autores principales:	Giulia Romano, Nikola Holodkov, Raffaella Klima, Fabian Feiguin
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/d38a7f08a17f4f109dbbf7984726cbf1
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spelling	oai:doaj.org-article:d38a7f08a17f4f109dbbf7984726cbf12021-12-02T15:15:04ZTDP-43 regulates GAD1 mRNA splicing and GABA signaling in Drosophila CNS10.1038/s41598-021-98241-z2045-2322https://doaj.org/article/d38a7f08a17f4f109dbbf7984726cbf12021-09-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-98241-zhttps://doaj.org/toc/2045-2322Abstract Alterations in the function of the RNA-binding protein TDP-43 are largely associated with the pathogenesis of amyotrophic lateral sclerosis (ALS), a devastating disease of the human motor system that leads to motoneurons degeneration and reduced life expectancy by molecular mechanisms not well known. In our previous work, we found that the expression levels of the glutamic acid decarboxylase enzyme (GAD1), responsible for converting glutamate to γ-aminobutyric acid (GABA), were downregulated in TBPH-null flies and motoneurons derived from ALS patients carrying mutations in TDP-43, suggesting that defects in the regulation of GAD1 may lead to neurodegeneration by affecting neurotransmitter balance. In this study, we observed that TBPH was required for the regulation of GAD1 pre-mRNA splicing and the levels of GABA in the Drosophila central nervous system (CNS). Interestingly, we discovered that pharmacological treatments aimed to potentiate GABA neurotransmission were able to revert locomotion deficiencies in TBPH-minus flies, revealing novel mechanisms and therapeutic strategies in ALS.Giulia RomanoNikola HolodkovRaffaella KlimaFabian FeiguinNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-8 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Giulia Romano Nikola Holodkov Raffaella Klima Fabian Feiguin TDP-43 regulates GAD1 mRNA splicing and GABA signaling in Drosophila CNS
description	Abstract Alterations in the function of the RNA-binding protein TDP-43 are largely associated with the pathogenesis of amyotrophic lateral sclerosis (ALS), a devastating disease of the human motor system that leads to motoneurons degeneration and reduced life expectancy by molecular mechanisms not well known. In our previous work, we found that the expression levels of the glutamic acid decarboxylase enzyme (GAD1), responsible for converting glutamate to γ-aminobutyric acid (GABA), were downregulated in TBPH-null flies and motoneurons derived from ALS patients carrying mutations in TDP-43, suggesting that defects in the regulation of GAD1 may lead to neurodegeneration by affecting neurotransmitter balance. In this study, we observed that TBPH was required for the regulation of GAD1 pre-mRNA splicing and the levels of GABA in the Drosophila central nervous system (CNS). Interestingly, we discovered that pharmacological treatments aimed to potentiate GABA neurotransmission were able to revert locomotion deficiencies in TBPH-minus flies, revealing novel mechanisms and therapeutic strategies in ALS.
format	article
author	Giulia Romano Nikola Holodkov Raffaella Klima Fabian Feiguin
author_facet	Giulia Romano Nikola Holodkov Raffaella Klima Fabian Feiguin
author_sort	Giulia Romano
title	TDP-43 regulates GAD1 mRNA splicing and GABA signaling in Drosophila CNS
title_short	TDP-43 regulates GAD1 mRNA splicing and GABA signaling in Drosophila CNS
title_full	TDP-43 regulates GAD1 mRNA splicing and GABA signaling in Drosophila CNS
title_fullStr	TDP-43 regulates GAD1 mRNA splicing and GABA signaling in Drosophila CNS
title_full_unstemmed	TDP-43 regulates GAD1 mRNA splicing and GABA signaling in Drosophila CNS
title_sort	tdp-43 regulates gad1 mrna splicing and gaba signaling in drosophila cns
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/d38a7f08a17f4f109dbbf7984726cbf1
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TDP-43 regulates GAD1 mRNA splicing and GABA signaling in Drosophila CNS

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