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,...

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Autores principales:	Sarah J Parker, Jodi Meyerowitz, Janine L James, Jeffrey R Liddell, Takashi Nonaka, Masato Hasegawa, Katja M Kanninen, SinChun Lim, Brett M Paterson, Paul S Donnelly, Peter J Crouch, Anthony R White
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/3b5512010cb641b9b53449d57880b60f
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spelling	oai:doaj.org-article:3b5512010cb641b9b53449d57880b60f2021-11-18T07:09:48ZInhibition of TDP-43 accumulation by bis(thiosemicarbazonato)-copper complexes.1932-620310.1371/journal.pone.0042277https://doaj.org/article/3b5512010cb641b9b53449d57880b60f2012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22879928/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Amyotrophic 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.Sarah J ParkerJodi MeyerowitzJanine L JamesJeffrey R LiddellTakashi NonakaMasato HasegawaKatja M KanninenSinChun LimBrett M PatersonPaul S DonnellyPeter J CrouchAnthony R WhitePublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 8, p e42277 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Sarah J Parker Jodi Meyerowitz Janine L James Jeffrey R Liddell Takashi Nonaka Masato Hasegawa Katja M Kanninen SinChun Lim Brett M Paterson Paul S Donnelly Peter J Crouch Anthony R White Inhibition of TDP-43 accumulation by bis(thiosemicarbazonato)-copper complexes.
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	article
author	Sarah J Parker Jodi Meyerowitz Janine L James Jeffrey R Liddell Takashi Nonaka Masato Hasegawa Katja M Kanninen SinChun Lim Brett M Paterson Paul S Donnelly Peter J Crouch Anthony R White
author_facet	Sarah J Parker Jodi Meyerowitz Janine L James Jeffrey R Liddell Takashi Nonaka Masato Hasegawa Katja M Kanninen SinChun Lim Brett M Paterson Paul S Donnelly Peter J Crouch Anthony R White
author_sort	Sarah J Parker
title	Inhibition of TDP-43 accumulation by bis(thiosemicarbazonato)-copper complexes.
title_short	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_sort	inhibition of tdp-43 accumulation by bis(thiosemicarbazonato)-copper complexes.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/3b5512010cb641b9b53449d57880b60f
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Inhibition of TDP-43 accumulation by bis(thiosemicarbazonato)-copper complexes.

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