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Axonal TDP-43 condensates drive neuromuscular junction disruption through inhibition of local synthesis of nuclear encoded mitochondrial proteins
Mislocalization of the predominantly nuclear RNA/DNA binding protein, TDP-43, occurs in motor neurons of ~95% of amyotrophic lateral sclerosis (ALS) patients, but the contribution of axonal TDP-43 to this neurodegenerative disease is unclear. Here, we show TDP-43 accumulation in intra-muscular nerve...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8617040/ https://www.ncbi.nlm.nih.gov/pubmed/34824257 http://dx.doi.org/10.1038/s41467-021-27221-8 |
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author | Altman, Topaz Ionescu, Ariel Ibraheem, Amjad Priesmann, Dominik Gradus-Pery, Tal Farberov, Luba Alexandra, Gayster Shelestovich, Natalia Dafinca, Ruxandra Shomron, Noam Rage, Florence Talbot, Kevin Ward, Michael E. Dori, Amir Krüger, Marcus Perlson, Eran |
author_facet | Altman, Topaz Ionescu, Ariel Ibraheem, Amjad Priesmann, Dominik Gradus-Pery, Tal Farberov, Luba Alexandra, Gayster Shelestovich, Natalia Dafinca, Ruxandra Shomron, Noam Rage, Florence Talbot, Kevin Ward, Michael E. Dori, Amir Krüger, Marcus Perlson, Eran |
author_sort | Altman, Topaz |
collection | PubMed |
description | Mislocalization of the predominantly nuclear RNA/DNA binding protein, TDP-43, occurs in motor neurons of ~95% of amyotrophic lateral sclerosis (ALS) patients, but the contribution of axonal TDP-43 to this neurodegenerative disease is unclear. Here, we show TDP-43 accumulation in intra-muscular nerves from ALS patients and in axons of human iPSC-derived motor neurons of ALS patient, as well as in motor neurons and neuromuscular junctions (NMJs) of a TDP-43 mislocalization mouse model. In axons, TDP-43 is hyper-phosphorylated and promotes G3BP1-positive ribonucleoprotein (RNP) condensate assembly, consequently inhibiting local protein synthesis in distal axons and NMJs. Specifically, the axonal and synaptic levels of nuclear-encoded mitochondrial proteins are reduced. Clearance of axonal TDP-43 or dissociation of G3BP1 condensates restored local translation and resolved TDP-43-derived toxicity in both axons and NMJs. These findings support an axonal gain of function of TDP-43 in ALS, which can be targeted for therapeutic development. |
format | Online Article Text |
id | pubmed-8617040 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-86170402021-12-10 Axonal TDP-43 condensates drive neuromuscular junction disruption through inhibition of local synthesis of nuclear encoded mitochondrial proteins Altman, Topaz Ionescu, Ariel Ibraheem, Amjad Priesmann, Dominik Gradus-Pery, Tal Farberov, Luba Alexandra, Gayster Shelestovich, Natalia Dafinca, Ruxandra Shomron, Noam Rage, Florence Talbot, Kevin Ward, Michael E. Dori, Amir Krüger, Marcus Perlson, Eran Nat Commun Article Mislocalization of the predominantly nuclear RNA/DNA binding protein, TDP-43, occurs in motor neurons of ~95% of amyotrophic lateral sclerosis (ALS) patients, but the contribution of axonal TDP-43 to this neurodegenerative disease is unclear. Here, we show TDP-43 accumulation in intra-muscular nerves from ALS patients and in axons of human iPSC-derived motor neurons of ALS patient, as well as in motor neurons and neuromuscular junctions (NMJs) of a TDP-43 mislocalization mouse model. In axons, TDP-43 is hyper-phosphorylated and promotes G3BP1-positive ribonucleoprotein (RNP) condensate assembly, consequently inhibiting local protein synthesis in distal axons and NMJs. Specifically, the axonal and synaptic levels of nuclear-encoded mitochondrial proteins are reduced. Clearance of axonal TDP-43 or dissociation of G3BP1 condensates restored local translation and resolved TDP-43-derived toxicity in both axons and NMJs. These findings support an axonal gain of function of TDP-43 in ALS, which can be targeted for therapeutic development. Nature Publishing Group UK 2021-11-25 /pmc/articles/PMC8617040/ /pubmed/34824257 http://dx.doi.org/10.1038/s41467-021-27221-8 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/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/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Altman, Topaz Ionescu, Ariel Ibraheem, Amjad Priesmann, Dominik Gradus-Pery, Tal Farberov, Luba Alexandra, Gayster Shelestovich, Natalia Dafinca, Ruxandra Shomron, Noam Rage, Florence Talbot, Kevin Ward, Michael E. Dori, Amir Krüger, Marcus Perlson, Eran Axonal TDP-43 condensates drive neuromuscular junction disruption through inhibition of local synthesis of nuclear encoded mitochondrial proteins |
title | Axonal TDP-43 condensates drive neuromuscular junction disruption through inhibition of local synthesis of nuclear encoded mitochondrial proteins |
title_full | Axonal TDP-43 condensates drive neuromuscular junction disruption through inhibition of local synthesis of nuclear encoded mitochondrial proteins |
title_fullStr | Axonal TDP-43 condensates drive neuromuscular junction disruption through inhibition of local synthesis of nuclear encoded mitochondrial proteins |
title_full_unstemmed | Axonal TDP-43 condensates drive neuromuscular junction disruption through inhibition of local synthesis of nuclear encoded mitochondrial proteins |
title_short | Axonal TDP-43 condensates drive neuromuscular junction disruption through inhibition of local synthesis of nuclear encoded mitochondrial proteins |
title_sort | axonal tdp-43 condensates drive neuromuscular junction disruption through inhibition of local synthesis of nuclear encoded mitochondrial proteins |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8617040/ https://www.ncbi.nlm.nih.gov/pubmed/34824257 http://dx.doi.org/10.1038/s41467-021-27221-8 |
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