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Inhibition of TDP-43 Accumulation by Bis(thiosemicarbazonato)-Copper Complexes
Amyotrophic lateral sclerosis (ALS) is a progressive, fatal, motor neuron disease with no effective long-term treatment options. Recently, TDP-43 has been identified as a key protein in the pathogenesis of some cases of ALS. Although the role of TDP-43 in motor neuron degeneration is not yet known,...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3411774/ https://www.ncbi.nlm.nih.gov/pubmed/22879928 http://dx.doi.org/10.1371/journal.pone.0042277 |
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author | Parker, Sarah J. Meyerowitz, Jodi James, Janine L. Liddell, Jeffrey R. Nonaka, Takashi Hasegawa, Masato Kanninen, Katja M. Lim, SinChun Paterson, Brett M. Donnelly, Paul S. Crouch, Peter J. White, Anthony R. |
author_facet | Parker, Sarah J. Meyerowitz, Jodi James, Janine L. Liddell, Jeffrey R. Nonaka, Takashi Hasegawa, Masato Kanninen, Katja M. Lim, SinChun Paterson, Brett M. Donnelly, Paul S. Crouch, Peter J. White, Anthony R. |
author_sort | Parker, Sarah J. |
collection | PubMed |
description | Amyotrophic lateral sclerosis (ALS) is a progressive, fatal, motor neuron disease with no effective long-term treatment options. Recently, TDP-43 has been identified as a key protein in the pathogenesis of some cases of ALS. Although the role of TDP-43 in motor neuron degeneration is not yet known, TDP-43 has been shown to accumulate in RNA stress granules (SGs) in cell models and in spinal cord tissue from ALS patients. The SG association may be an early pathological change to TDP-43 metabolism and as such a potential target for therapeutic intervention. Accumulation of TDP-43 in SGs induced by inhibition of mitochondrial activity can be inhibited by modulation of cellular kinase activity. We have also found that treatment of cells and animal models of neurodegeneration, including an ALS model, with bioavailable bis(thiosemicarbazonato)copper(II) complexes (Cu(II)(btsc)s) can modulate kinase activity and induce neuroprotective effects. In this study we examined the effect of diacetylbis(-methylthiosemicarbazonato)copper(II) (Cu(II)(atsm)) and glyoxalbis(-methylthiosemicarbazonato)copper(II) (Cu(II)(gtsm)) on TDP-43-positive SGs induced in SH-SY5Y cells in culture. We found that the Cu(II)(btsc)s blocked formation of TDP-43-and human antigen R (HuR)-positive SGs induced by paraquat. The Cu(II)(btsc)s protected neurons from paraquat-mediated cell death. These effects were associated with inhibition of ERK phosphorylation. Co-treatment of cultures with either Cu(II)(atsm) or an ERK inhibitor, PD98059 both prevented ERK activation and blocked formation of TDP-43-and HuR-positive SGs. Cu(II)(atsm) treatment or ERK inhibition also prevented abnormal ubiquitin accumulation in paraquat-treated cells suggesting a link between prolonged ERK activation and abnormal ubiquitin metabolism in paraquat stress and inhibition by Cu. Moreover, Cu(II)(atsm) reduced accumulation of C-terminal (219–414) TDP-43 in transfected SH-SY5Y cells. These results demonstrate that Cu(II)(btsc) complexes could potentially be developed as a neuroprotective agent to modulate neuronal kinase function and inhibit TDP-43 aggregation. Further studies in TDP-43 animal models are warranted. |
format | Online Article Text |
id | pubmed-3411774 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-34117742012-08-09 Inhibition of TDP-43 Accumulation by Bis(thiosemicarbazonato)-Copper Complexes Parker, Sarah J. Meyerowitz, Jodi James, Janine L. Liddell, Jeffrey R. Nonaka, Takashi Hasegawa, Masato Kanninen, Katja M. Lim, SinChun Paterson, Brett M. Donnelly, Paul S. Crouch, Peter J. White, Anthony R. PLoS One Research Article Amyotrophic lateral sclerosis (ALS) is a progressive, fatal, motor neuron disease with no effective long-term treatment options. Recently, TDP-43 has been identified as a key protein in the pathogenesis of some cases of ALS. Although the role of TDP-43 in motor neuron degeneration is not yet known, TDP-43 has been shown to accumulate in RNA stress granules (SGs) in cell models and in spinal cord tissue from ALS patients. The SG association may be an early pathological change to TDP-43 metabolism and as such a potential target for therapeutic intervention. Accumulation of TDP-43 in SGs induced by inhibition of mitochondrial activity can be inhibited by modulation of cellular kinase activity. We have also found that treatment of cells and animal models of neurodegeneration, including an ALS model, with bioavailable bis(thiosemicarbazonato)copper(II) complexes (Cu(II)(btsc)s) can modulate kinase activity and induce neuroprotective effects. In this study we examined the effect of diacetylbis(-methylthiosemicarbazonato)copper(II) (Cu(II)(atsm)) and glyoxalbis(-methylthiosemicarbazonato)copper(II) (Cu(II)(gtsm)) on TDP-43-positive SGs induced in SH-SY5Y cells in culture. We found that the Cu(II)(btsc)s blocked formation of TDP-43-and human antigen R (HuR)-positive SGs induced by paraquat. The Cu(II)(btsc)s protected neurons from paraquat-mediated cell death. These effects were associated with inhibition of ERK phosphorylation. Co-treatment of cultures with either Cu(II)(atsm) or an ERK inhibitor, PD98059 both prevented ERK activation and blocked formation of TDP-43-and HuR-positive SGs. Cu(II)(atsm) treatment or ERK inhibition also prevented abnormal ubiquitin accumulation in paraquat-treated cells suggesting a link between prolonged ERK activation and abnormal ubiquitin metabolism in paraquat stress and inhibition by Cu. Moreover, Cu(II)(atsm) reduced accumulation of C-terminal (219–414) TDP-43 in transfected SH-SY5Y cells. These results demonstrate that Cu(II)(btsc) complexes could potentially be developed as a neuroprotective agent to modulate neuronal kinase function and inhibit TDP-43 aggregation. Further studies in TDP-43 animal models are warranted. Public Library of Science 2012-08-03 /pmc/articles/PMC3411774/ /pubmed/22879928 http://dx.doi.org/10.1371/journal.pone.0042277 Text en © 2012 Parker 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 Parker, Sarah J. Meyerowitz, Jodi James, Janine L. Liddell, Jeffrey R. Nonaka, Takashi Hasegawa, Masato Kanninen, Katja M. Lim, SinChun Paterson, Brett M. Donnelly, Paul S. Crouch, Peter J. White, Anthony R. Inhibition of TDP-43 Accumulation by Bis(thiosemicarbazonato)-Copper Complexes |
title | Inhibition of TDP-43 Accumulation by Bis(thiosemicarbazonato)-Copper Complexes |
title_full | Inhibition of TDP-43 Accumulation by Bis(thiosemicarbazonato)-Copper Complexes |
title_fullStr | Inhibition of TDP-43 Accumulation by Bis(thiosemicarbazonato)-Copper Complexes |
title_full_unstemmed | Inhibition of TDP-43 Accumulation by Bis(thiosemicarbazonato)-Copper Complexes |
title_short | Inhibition of TDP-43 Accumulation by Bis(thiosemicarbazonato)-Copper Complexes |
title_sort | inhibition of tdp-43 accumulation by bis(thiosemicarbazonato)-copper complexes |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3411774/ https://www.ncbi.nlm.nih.gov/pubmed/22879928 http://dx.doi.org/10.1371/journal.pone.0042277 |
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