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Cytoplasmic Accumulation and Aggregation of TDP-43 upon Proteasome Inhibition in Cultured Neurons

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are characterized by intraneuronal deposition of the nuclear TAR DNA-binding protein 43 (TDP-43) caused by unknown mechanisms. Here, we studied TDP-43 in primary neurons under different stress conditions and found that...

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Autores principales: van Eersel, Janet, Ke, Yazi D., Gladbach, Amadeus, Bi, Mian, Götz, Jürgen, Kril, Jillian J., Ittner, Lars M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3146516/
https://www.ncbi.nlm.nih.gov/pubmed/21829535
http://dx.doi.org/10.1371/journal.pone.0022850
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author van Eersel, Janet
Ke, Yazi D.
Gladbach, Amadeus
Bi, Mian
Götz, Jürgen
Kril, Jillian J.
Ittner, Lars M.
author_facet van Eersel, Janet
Ke, Yazi D.
Gladbach, Amadeus
Bi, Mian
Götz, Jürgen
Kril, Jillian J.
Ittner, Lars M.
author_sort van Eersel, Janet
collection PubMed
description Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are characterized by intraneuronal deposition of the nuclear TAR DNA-binding protein 43 (TDP-43) caused by unknown mechanisms. Here, we studied TDP-43 in primary neurons under different stress conditions and found that only proteasome inhibition by MG-132 or lactacystin could induce significant cytoplasmic accumulation of TDP-43, a histopathological hallmark in disease. This cytoplasmic accumulation was accompanied by phosphorylation, ubiquitination and aggregation of TDP-43, recapitulating major features of disease. Proteasome inhibition produced similar effects in both hippocampal and cortical neurons, as well as in immortalized motor neurons. To determine the contribution of TDP-43 to cell death, we reduced TDP-43 expression using small interfering RNA (siRNA), and found that reduced levels of TDP-43 dose-dependently rendered neurons more vulnerable to MG-132. Taken together, our data suggests a role for the proteasome in subcellular localization of TDP-43, and possibly in disease.
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spelling pubmed-31465162011-08-09 Cytoplasmic Accumulation and Aggregation of TDP-43 upon Proteasome Inhibition in Cultured Neurons van Eersel, Janet Ke, Yazi D. Gladbach, Amadeus Bi, Mian Götz, Jürgen Kril, Jillian J. Ittner, Lars M. PLoS One Research Article Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are characterized by intraneuronal deposition of the nuclear TAR DNA-binding protein 43 (TDP-43) caused by unknown mechanisms. Here, we studied TDP-43 in primary neurons under different stress conditions and found that only proteasome inhibition by MG-132 or lactacystin could induce significant cytoplasmic accumulation of TDP-43, a histopathological hallmark in disease. This cytoplasmic accumulation was accompanied by phosphorylation, ubiquitination and aggregation of TDP-43, recapitulating major features of disease. Proteasome inhibition produced similar effects in both hippocampal and cortical neurons, as well as in immortalized motor neurons. To determine the contribution of TDP-43 to cell death, we reduced TDP-43 expression using small interfering RNA (siRNA), and found that reduced levels of TDP-43 dose-dependently rendered neurons more vulnerable to MG-132. Taken together, our data suggests a role for the proteasome in subcellular localization of TDP-43, and possibly in disease. Public Library of Science 2011-07-29 /pmc/articles/PMC3146516/ /pubmed/21829535 http://dx.doi.org/10.1371/journal.pone.0022850 Text en van Eersel et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
van Eersel, Janet
Ke, Yazi D.
Gladbach, Amadeus
Bi, Mian
Götz, Jürgen
Kril, Jillian J.
Ittner, Lars M.
Cytoplasmic Accumulation and Aggregation of TDP-43 upon Proteasome Inhibition in Cultured Neurons
title Cytoplasmic Accumulation and Aggregation of TDP-43 upon Proteasome Inhibition in Cultured Neurons
title_full Cytoplasmic Accumulation and Aggregation of TDP-43 upon Proteasome Inhibition in Cultured Neurons
title_fullStr Cytoplasmic Accumulation and Aggregation of TDP-43 upon Proteasome Inhibition in Cultured Neurons
title_full_unstemmed Cytoplasmic Accumulation and Aggregation of TDP-43 upon Proteasome Inhibition in Cultured Neurons
title_short Cytoplasmic Accumulation and Aggregation of TDP-43 upon Proteasome Inhibition in Cultured Neurons
title_sort cytoplasmic accumulation and aggregation of tdp-43 upon proteasome inhibition in cultured neurons
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3146516/
https://www.ncbi.nlm.nih.gov/pubmed/21829535
http://dx.doi.org/10.1371/journal.pone.0022850
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