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Unraveling the toxic effects mediated by the neurodegenerative disease–associated S375G mutation of TDP-43 and its S375E phosphomimetic variant
TAR DNA-binding protein 43 (TDP-43) is a nucleic acid–binding protein found in the nucleus that accumulates in the cytoplasm under pathological conditions, leading to proteinopathies, such as frontotemporal dementia and ALS. An emerging area of TDP-43 research is represented by the study of its post...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Biochemistry and Molecular Biology
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9364110/ https://www.ncbi.nlm.nih.gov/pubmed/35835219 http://dx.doi.org/10.1016/j.jbc.2022.102252 |
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author | Paron, Francesca Barattucci, Simone Cappelli, Sara Romano, Maurizio Berlingieri, Christian Stuani, Cristiana Laurents, Douglas Mompeán, Miguel Buratti, Emanuele |
author_facet | Paron, Francesca Barattucci, Simone Cappelli, Sara Romano, Maurizio Berlingieri, Christian Stuani, Cristiana Laurents, Douglas Mompeán, Miguel Buratti, Emanuele |
author_sort | Paron, Francesca |
collection | PubMed |
description | TAR DNA-binding protein 43 (TDP-43) is a nucleic acid–binding protein found in the nucleus that accumulates in the cytoplasm under pathological conditions, leading to proteinopathies, such as frontotemporal dementia and ALS. An emerging area of TDP-43 research is represented by the study of its post-translational modifications, the way they are connected to disease-associated mutations, and what this means for pathological processes. Recently, we described a novel mutation in TDP-43 in an early onset ALS case that was affecting a potential phosphorylation site in position 375 (S375G). A preliminary characterization showed that both the S375G mutation and its phosphomimetic variant, S375E, displayed altered nuclear–cytoplasmic distribution and cellular toxicity. To better investigate these effects, here we established cell lines expressing inducible WT, S375G, and S375E TDP-43 variants. Interestingly, we found that these mutants do not seem to affect well-studied aspects of TDP-43, such as RNA splicing or autoregulation, or protein conformation, dynamics, or aggregation, although they do display dysmorphic nuclear shape and cell cycle alterations. In addition, RNA-Seq analysis of these cell lines showed that although the disease-associated S375G mutation and its phosphomimetic S375E variant regulate distinct sets of genes, they have a common target in mitochondrial apoptotic genes. Taken together, our data strongly support the growing evidence that alterations in TDP-43 post-translational modifications can play a potentially important role in disease pathogenesis and provide a further link between TDP-43 pathology and mitochondrial health. |
format | Online Article Text |
id | pubmed-9364110 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Society for Biochemistry and Molecular Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-93641102022-08-11 Unraveling the toxic effects mediated by the neurodegenerative disease–associated S375G mutation of TDP-43 and its S375E phosphomimetic variant Paron, Francesca Barattucci, Simone Cappelli, Sara Romano, Maurizio Berlingieri, Christian Stuani, Cristiana Laurents, Douglas Mompeán, Miguel Buratti, Emanuele J Biol Chem Research Article TAR DNA-binding protein 43 (TDP-43) is a nucleic acid–binding protein found in the nucleus that accumulates in the cytoplasm under pathological conditions, leading to proteinopathies, such as frontotemporal dementia and ALS. An emerging area of TDP-43 research is represented by the study of its post-translational modifications, the way they are connected to disease-associated mutations, and what this means for pathological processes. Recently, we described a novel mutation in TDP-43 in an early onset ALS case that was affecting a potential phosphorylation site in position 375 (S375G). A preliminary characterization showed that both the S375G mutation and its phosphomimetic variant, S375E, displayed altered nuclear–cytoplasmic distribution and cellular toxicity. To better investigate these effects, here we established cell lines expressing inducible WT, S375G, and S375E TDP-43 variants. Interestingly, we found that these mutants do not seem to affect well-studied aspects of TDP-43, such as RNA splicing or autoregulation, or protein conformation, dynamics, or aggregation, although they do display dysmorphic nuclear shape and cell cycle alterations. In addition, RNA-Seq analysis of these cell lines showed that although the disease-associated S375G mutation and its phosphomimetic S375E variant regulate distinct sets of genes, they have a common target in mitochondrial apoptotic genes. Taken together, our data strongly support the growing evidence that alterations in TDP-43 post-translational modifications can play a potentially important role in disease pathogenesis and provide a further link between TDP-43 pathology and mitochondrial health. American Society for Biochemistry and Molecular Biology 2022-07-12 /pmc/articles/PMC9364110/ /pubmed/35835219 http://dx.doi.org/10.1016/j.jbc.2022.102252 Text en © 2022 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Research Article Paron, Francesca Barattucci, Simone Cappelli, Sara Romano, Maurizio Berlingieri, Christian Stuani, Cristiana Laurents, Douglas Mompeán, Miguel Buratti, Emanuele Unraveling the toxic effects mediated by the neurodegenerative disease–associated S375G mutation of TDP-43 and its S375E phosphomimetic variant |
title | Unraveling the toxic effects mediated by the neurodegenerative disease–associated S375G mutation of TDP-43 and its S375E phosphomimetic variant |
title_full | Unraveling the toxic effects mediated by the neurodegenerative disease–associated S375G mutation of TDP-43 and its S375E phosphomimetic variant |
title_fullStr | Unraveling the toxic effects mediated by the neurodegenerative disease–associated S375G mutation of TDP-43 and its S375E phosphomimetic variant |
title_full_unstemmed | Unraveling the toxic effects mediated by the neurodegenerative disease–associated S375G mutation of TDP-43 and its S375E phosphomimetic variant |
title_short | Unraveling the toxic effects mediated by the neurodegenerative disease–associated S375G mutation of TDP-43 and its S375E phosphomimetic variant |
title_sort | unraveling the toxic effects mediated by the neurodegenerative disease–associated s375g mutation of tdp-43 and its s375e phosphomimetic variant |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9364110/ https://www.ncbi.nlm.nih.gov/pubmed/35835219 http://dx.doi.org/10.1016/j.jbc.2022.102252 |
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