Cargando…

Deregulation of TDP-43 in amyotrophic lateral sclerosis triggers nuclear factor κB–mediated pathogenic pathways

TDP-43 (TAR DNA-binding protein 43) inclusions are a hallmark of amyotrophic lateral sclerosis (ALS). In this study, we report that TDP-43 and nuclear factor κB (NF-κB) p65 messenger RNA and protein expression is higher in spinal cords in ALS patients than healthy individuals. TDP-43 interacts with...

Descripción completa

Detalles Bibliográficos
Autores principales: Swarup, Vivek, Phaneuf, Daniel, Dupré, Nicolas, Petri, Susanne, Strong, Michael, Kriz, Jasna, Julien, Jean-Pierre
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3256969/
https://www.ncbi.nlm.nih.gov/pubmed/22084410
http://dx.doi.org/10.1084/jem.20111313
_version_ 1782221084066578432
author Swarup, Vivek
Phaneuf, Daniel
Dupré, Nicolas
Petri, Susanne
Strong, Michael
Kriz, Jasna
Julien, Jean-Pierre
author_facet Swarup, Vivek
Phaneuf, Daniel
Dupré, Nicolas
Petri, Susanne
Strong, Michael
Kriz, Jasna
Julien, Jean-Pierre
author_sort Swarup, Vivek
collection PubMed
description TDP-43 (TAR DNA-binding protein 43) inclusions are a hallmark of amyotrophic lateral sclerosis (ALS). In this study, we report that TDP-43 and nuclear factor κB (NF-κB) p65 messenger RNA and protein expression is higher in spinal cords in ALS patients than healthy individuals. TDP-43 interacts with and colocalizes with p65 in glial and neuronal cells from ALS patients and mice expressing wild-type and mutant TDP-43 transgenes but not in cells from healthy individuals or nontransgenic mice. TDP-43 acted as a co-activator of p65, and glial cells expressing higher amounts of TDP-43 produced more proinflammatory cytokines and neurotoxic mediators after stimulation with lipopolysaccharide or reactive oxygen species. TDP-43 overexpression in neurons also increased their vulnerability to toxic mediators. Treatment of TDP-43 mice with Withaferin A, an inhibitor of NF-κB activity, reduced denervation in the neuromuscular junction and ALS disease symptoms. We propose that TDP-43 deregulation contributes to ALS pathogenesis in part by enhancing NF-κB activation and that NF-κB may constitute a therapeutic target for the disease.
format Online
Article
Text
id pubmed-3256969
institution National Center for Biotechnology Information
language English
publishDate 2011
publisher The Rockefeller University Press
record_format MEDLINE/PubMed
spelling pubmed-32569692012-05-21 Deregulation of TDP-43 in amyotrophic lateral sclerosis triggers nuclear factor κB–mediated pathogenic pathways Swarup, Vivek Phaneuf, Daniel Dupré, Nicolas Petri, Susanne Strong, Michael Kriz, Jasna Julien, Jean-Pierre J Exp Med Article TDP-43 (TAR DNA-binding protein 43) inclusions are a hallmark of amyotrophic lateral sclerosis (ALS). In this study, we report that TDP-43 and nuclear factor κB (NF-κB) p65 messenger RNA and protein expression is higher in spinal cords in ALS patients than healthy individuals. TDP-43 interacts with and colocalizes with p65 in glial and neuronal cells from ALS patients and mice expressing wild-type and mutant TDP-43 transgenes but not in cells from healthy individuals or nontransgenic mice. TDP-43 acted as a co-activator of p65, and glial cells expressing higher amounts of TDP-43 produced more proinflammatory cytokines and neurotoxic mediators after stimulation with lipopolysaccharide or reactive oxygen species. TDP-43 overexpression in neurons also increased their vulnerability to toxic mediators. Treatment of TDP-43 mice with Withaferin A, an inhibitor of NF-κB activity, reduced denervation in the neuromuscular junction and ALS disease symptoms. We propose that TDP-43 deregulation contributes to ALS pathogenesis in part by enhancing NF-κB activation and that NF-κB may constitute a therapeutic target for the disease. The Rockefeller University Press 2011-11-21 /pmc/articles/PMC3256969/ /pubmed/22084410 http://dx.doi.org/10.1084/jem.20111313 Text en © 2011 Swarup et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Article
Swarup, Vivek
Phaneuf, Daniel
Dupré, Nicolas
Petri, Susanne
Strong, Michael
Kriz, Jasna
Julien, Jean-Pierre
Deregulation of TDP-43 in amyotrophic lateral sclerosis triggers nuclear factor κB–mediated pathogenic pathways
title Deregulation of TDP-43 in amyotrophic lateral sclerosis triggers nuclear factor κB–mediated pathogenic pathways
title_full Deregulation of TDP-43 in amyotrophic lateral sclerosis triggers nuclear factor κB–mediated pathogenic pathways
title_fullStr Deregulation of TDP-43 in amyotrophic lateral sclerosis triggers nuclear factor κB–mediated pathogenic pathways
title_full_unstemmed Deregulation of TDP-43 in amyotrophic lateral sclerosis triggers nuclear factor κB–mediated pathogenic pathways
title_short Deregulation of TDP-43 in amyotrophic lateral sclerosis triggers nuclear factor κB–mediated pathogenic pathways
title_sort deregulation of tdp-43 in amyotrophic lateral sclerosis triggers nuclear factor κb–mediated pathogenic pathways
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3256969/
https://www.ncbi.nlm.nih.gov/pubmed/22084410
http://dx.doi.org/10.1084/jem.20111313
work_keys_str_mv AT swarupvivek deregulationoftdp43inamyotrophiclateralsclerosistriggersnuclearfactorkbmediatedpathogenicpathways
AT phaneufdaniel deregulationoftdp43inamyotrophiclateralsclerosistriggersnuclearfactorkbmediatedpathogenicpathways
AT duprenicolas deregulationoftdp43inamyotrophiclateralsclerosistriggersnuclearfactorkbmediatedpathogenicpathways
AT petrisusanne deregulationoftdp43inamyotrophiclateralsclerosistriggersnuclearfactorkbmediatedpathogenicpathways
AT strongmichael deregulationoftdp43inamyotrophiclateralsclerosistriggersnuclearfactorkbmediatedpathogenicpathways
AT krizjasna deregulationoftdp43inamyotrophiclateralsclerosistriggersnuclearfactorkbmediatedpathogenicpathways
AT julienjeanpierre deregulationoftdp43inamyotrophiclateralsclerosistriggersnuclearfactorkbmediatedpathogenicpathways