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Loss of Tdp-43 disrupts the axonal transcriptome of motoneurons accompanied by impaired axonal translation and mitochondria function

Protein inclusions containing the RNA-binding protein TDP-43 are a pathological hallmark of amyotrophic lateral sclerosis and other neurodegenerative disorders. The loss of TDP-43 function that is associated with these inclusions affects post-transcriptional processing of RNAs in multiple ways inclu...

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Autores principales: Briese, Michael, Saal-Bauernschubert, Lena, Lüningschrör, Patrick, Moradi, Mehri, Dombert, Benjamin, Surrey, Verena, Appenzeller, Silke, Deng, Chunchu, Jablonka, Sibylle, Sendtner, Michael
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2020
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7379803/
https://www.ncbi.nlm.nih.gov/pubmed/32709255
http://dx.doi.org/10.1186/s40478-020-00987-6
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author Briese, Michael
Saal-Bauernschubert, Lena
Lüningschrör, Patrick
Moradi, Mehri
Dombert, Benjamin
Surrey, Verena
Appenzeller, Silke
Deng, Chunchu
Jablonka, Sibylle
Sendtner, Michael
author_facet Briese, Michael
Saal-Bauernschubert, Lena
Lüningschrör, Patrick
Moradi, Mehri
Dombert, Benjamin
Surrey, Verena
Appenzeller, Silke
Deng, Chunchu
Jablonka, Sibylle
Sendtner, Michael
author_sort Briese, Michael
collection PubMed
description Protein inclusions containing the RNA-binding protein TDP-43 are a pathological hallmark of amyotrophic lateral sclerosis and other neurodegenerative disorders. The loss of TDP-43 function that is associated with these inclusions affects post-transcriptional processing of RNAs in multiple ways including pre-mRNA splicing, nucleocytoplasmic transport, modulation of mRNA stability and translation. In contrast, less is known about the role of TDP-43 in axonal RNA metabolism in motoneurons. Here we show that depletion of Tdp-43 in primary motoneurons affects axon growth. This defect is accompanied by subcellular transcriptome alterations in the axonal and somatodendritic compartment. The axonal localization of transcripts encoding components of the cytoskeleton, the translational machinery and transcripts involved in mitochondrial energy metabolism were particularly affected by loss of Tdp-43. Accordingly, we observed reduced protein synthesis and disturbed mitochondrial functions in axons of Tdp-43-depleted motoneurons. Treatment with nicotinamide rescued the axon growth defect associated with loss of Tdp-43. These results show that Tdp-43 depletion in motoneurons affects several pathways integral to axon health indicating that loss of TDP-43 function could thus make a major contribution to axonal pathomechanisms in ALS.
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spelling pubmed-73798032020-08-04 Loss of Tdp-43 disrupts the axonal transcriptome of motoneurons accompanied by impaired axonal translation and mitochondria function Briese, Michael Saal-Bauernschubert, Lena Lüningschrör, Patrick Moradi, Mehri Dombert, Benjamin Surrey, Verena Appenzeller, Silke Deng, Chunchu Jablonka, Sibylle Sendtner, Michael Acta Neuropathol Commun Research Protein inclusions containing the RNA-binding protein TDP-43 are a pathological hallmark of amyotrophic lateral sclerosis and other neurodegenerative disorders. The loss of TDP-43 function that is associated with these inclusions affects post-transcriptional processing of RNAs in multiple ways including pre-mRNA splicing, nucleocytoplasmic transport, modulation of mRNA stability and translation. In contrast, less is known about the role of TDP-43 in axonal RNA metabolism in motoneurons. Here we show that depletion of Tdp-43 in primary motoneurons affects axon growth. This defect is accompanied by subcellular transcriptome alterations in the axonal and somatodendritic compartment. The axonal localization of transcripts encoding components of the cytoskeleton, the translational machinery and transcripts involved in mitochondrial energy metabolism were particularly affected by loss of Tdp-43. Accordingly, we observed reduced protein synthesis and disturbed mitochondrial functions in axons of Tdp-43-depleted motoneurons. Treatment with nicotinamide rescued the axon growth defect associated with loss of Tdp-43. These results show that Tdp-43 depletion in motoneurons affects several pathways integral to axon health indicating that loss of TDP-43 function could thus make a major contribution to axonal pathomechanisms in ALS. BioMed Central 2020-07-24 /pmc/articles/PMC7379803/ /pubmed/32709255 http://dx.doi.org/10.1186/s40478-020-00987-6 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
Briese, Michael
Saal-Bauernschubert, Lena
Lüningschrör, Patrick
Moradi, Mehri
Dombert, Benjamin
Surrey, Verena
Appenzeller, Silke
Deng, Chunchu
Jablonka, Sibylle
Sendtner, Michael
Loss of Tdp-43 disrupts the axonal transcriptome of motoneurons accompanied by impaired axonal translation and mitochondria function
title Loss of Tdp-43 disrupts the axonal transcriptome of motoneurons accompanied by impaired axonal translation and mitochondria function
title_full Loss of Tdp-43 disrupts the axonal transcriptome of motoneurons accompanied by impaired axonal translation and mitochondria function
title_fullStr Loss of Tdp-43 disrupts the axonal transcriptome of motoneurons accompanied by impaired axonal translation and mitochondria function
title_full_unstemmed Loss of Tdp-43 disrupts the axonal transcriptome of motoneurons accompanied by impaired axonal translation and mitochondria function
title_short Loss of Tdp-43 disrupts the axonal transcriptome of motoneurons accompanied by impaired axonal translation and mitochondria function
title_sort loss of tdp-43 disrupts the axonal transcriptome of motoneurons accompanied by impaired axonal translation and mitochondria function
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7379803/
https://www.ncbi.nlm.nih.gov/pubmed/32709255
http://dx.doi.org/10.1186/s40478-020-00987-6
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