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TDP-43 prevents retrotransposon activation in the Drosophila motor system through regulation of Dicer-2 activity

BACKGROUND: Mutations in the small RNA-binding protein TDP-43 lead to the formation of insoluble cytoplasmic aggregates that have been associated with the onset and progression of amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder affecting homeostasis of the motor system which is als...

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Autores principales: Romano, Giulia, Klima, Raffaella, Feiguin, Fabian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334854/
https://www.ncbi.nlm.nih.gov/pubmed/32620127
http://dx.doi.org/10.1186/s12915-020-00816-1
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author Romano, Giulia
Klima, Raffaella
Feiguin, Fabian
author_facet Romano, Giulia
Klima, Raffaella
Feiguin, Fabian
author_sort Romano, Giulia
collection PubMed
description BACKGROUND: Mutations in the small RNA-binding protein TDP-43 lead to the formation of insoluble cytoplasmic aggregates that have been associated with the onset and progression of amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder affecting homeostasis of the motor system which is also characterized by aberrant expression of retrotransposable elements (RTEs). Although the TDP-43 function was shown to be required in the neurons and glia to maintain the organization of neuromuscular synapses and prevent denervation of the skeletal muscles, the molecular mechanisms involved in physiological dysregulation remain elusive. Here, we address this issue using a null mutation of the TDP-43 Drosophila homolog, TBPH. RESULTS: Using genome-wide gene expression profiles, we detected a strong upregulation of RTE expression in TBPH-null Drosophila heads, while the genetic rescue of the TDP-43 function reverted these modifications. Furthermore, we found that TBPH modulates the small interfering RNA (siRNA) silencing machinery responsible for RTE repression. Molecularly, we observed that TBPH regulates the expression levels of Dicer-2 by direct protein-mRNA interactions in vivo. Accordingly, the genetic or pharmacological recovery of Dicer-2 activity was sufficient to repress retrotransposon activation and promote motoneuron axonal wrapping and synaptic growth in TBPH-null Drosophila. CONCLUSIONS: We identified an upregulation of RTE expression in TBPH-null Drosophila heads and demonstrate that defects in the siRNA pathway lead to RTE upregulation and motoneuron degeneration. Our results describe a novel physiological role of endogenous TDP-43 in the prevention of RTE-induced neurological alterations through the modulation of Dicer-2 activity and the siRNA pathway.
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spelling pubmed-73348542020-07-06 TDP-43 prevents retrotransposon activation in the Drosophila motor system through regulation of Dicer-2 activity Romano, Giulia Klima, Raffaella Feiguin, Fabian BMC Biol Research Article BACKGROUND: Mutations in the small RNA-binding protein TDP-43 lead to the formation of insoluble cytoplasmic aggregates that have been associated with the onset and progression of amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder affecting homeostasis of the motor system which is also characterized by aberrant expression of retrotransposable elements (RTEs). Although the TDP-43 function was shown to be required in the neurons and glia to maintain the organization of neuromuscular synapses and prevent denervation of the skeletal muscles, the molecular mechanisms involved in physiological dysregulation remain elusive. Here, we address this issue using a null mutation of the TDP-43 Drosophila homolog, TBPH. RESULTS: Using genome-wide gene expression profiles, we detected a strong upregulation of RTE expression in TBPH-null Drosophila heads, while the genetic rescue of the TDP-43 function reverted these modifications. Furthermore, we found that TBPH modulates the small interfering RNA (siRNA) silencing machinery responsible for RTE repression. Molecularly, we observed that TBPH regulates the expression levels of Dicer-2 by direct protein-mRNA interactions in vivo. Accordingly, the genetic or pharmacological recovery of Dicer-2 activity was sufficient to repress retrotransposon activation and promote motoneuron axonal wrapping and synaptic growth in TBPH-null Drosophila. CONCLUSIONS: We identified an upregulation of RTE expression in TBPH-null Drosophila heads and demonstrate that defects in the siRNA pathway lead to RTE upregulation and motoneuron degeneration. Our results describe a novel physiological role of endogenous TDP-43 in the prevention of RTE-induced neurological alterations through the modulation of Dicer-2 activity and the siRNA pathway. BioMed Central 2020-07-03 /pmc/articles/PMC7334854/ /pubmed/32620127 http://dx.doi.org/10.1186/s12915-020-00816-1 Text en © The Author(s) 2020 Open AccessThis 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research Article
Romano, Giulia
Klima, Raffaella
Feiguin, Fabian
TDP-43 prevents retrotransposon activation in the Drosophila motor system through regulation of Dicer-2 activity
title TDP-43 prevents retrotransposon activation in the Drosophila motor system through regulation of Dicer-2 activity
title_full TDP-43 prevents retrotransposon activation in the Drosophila motor system through regulation of Dicer-2 activity
title_fullStr TDP-43 prevents retrotransposon activation in the Drosophila motor system through regulation of Dicer-2 activity
title_full_unstemmed TDP-43 prevents retrotransposon activation in the Drosophila motor system through regulation of Dicer-2 activity
title_short TDP-43 prevents retrotransposon activation in the Drosophila motor system through regulation of Dicer-2 activity
title_sort tdp-43 prevents retrotransposon activation in the drosophila motor system through regulation of dicer-2 activity
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334854/
https://www.ncbi.nlm.nih.gov/pubmed/32620127
http://dx.doi.org/10.1186/s12915-020-00816-1
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