Decreased glutathione accelerates neurological deficit and mitochondrial pathology in familial ALS-linked hSOD1G93A mice model

Dominant mutations in Cu/Zn-superoxide dismutase (SOD1) cause familial forms of amyotrophic lateral sclerosis (ALS), a fatal disorder characterized by the progressive loss of motor neurons. To investigate the role of antioxidant defenses in ALS we used knockout mice for the glutamate-cysteine ligase...

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Main Authors:	Marcelo R. Vargas, Delinda A. Johnson, Jeffrey A. Johnson
Format:	Article
Language:	English
Published:	Elsevier 2011-09-01
Series:	Neurobiology of Disease
Subjects:	Amyotrophic lateral sclerosis Glutathione GCLM Mitochondria
Online Access:	http://www.sciencedirect.com/science/article/pii/S0969996111001422

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spelling	doaj-0c749cf97a3548e3b3a4d64d2cf060372021-03-22T12:36:57ZengElsevierNeurobiology of Disease1095-953X2011-09-01433543551Decreased glutathione accelerates neurological deficit and mitochondrial pathology in familial ALS-linked hSOD1G93A mice modelMarcelo R. Vargas0Delinda A. Johnson1Jeffrey A. Johnson2Division of Pharmaceutical Sciences, University of Wisconsin, Madison, WI, USADivision of Pharmaceutical Sciences, University of Wisconsin, Madison, WI, USADivision of Pharmaceutical Sciences, University of Wisconsin, Madison, WI, USA; Waisman Center, University of Wisconsin, Madison, WI, USA; Molecular and Environmental Toxicology Center, University of Wisconsin, Madison, WI, USA; Center for Neuroscience, University of Wisconsin, Madison, WI, USA; Corresponding author at: School of Pharmacy, 6125 Rennebohm Hall, University of Wisconsin, Madison, WI, USA. Fax: +1 608 262 5345.Dominant mutations in Cu/Zn-superoxide dismutase (SOD1) cause familial forms of amyotrophic lateral sclerosis (ALS), a fatal disorder characterized by the progressive loss of motor neurons. To investigate the role of antioxidant defenses in ALS we used knockout mice for the glutamate-cysteine ligase modifier subunit (GCLM−/−), which have a 70–80% reduction in total glutathione. Although GCLM(−/−) mice are viable and fertile, the life span of GCLM(−/−)/hSOD1G93A mice decreased in 55% when compared to GCLM(+/+)/hSOD1G93A mice. Decreased life span in GCLM(−/−)/hSOD1G93A mice was associated to increased oxidative stress, aggravated mitochondrial pathology and increased association of hSOD1 with the mitochondria. Interestingly, when the GCLM(−/−) animals were mated with a different ALS-model which overexpress the experimental mutation hSOD1H46R/H48Q, no effect was observed in survival of GCLM(−/−)/hSOD1H46R/H48Q mice; and little or no mitochondrial pathology was observed. Since a specific disease modifier, such as glutathione deficiency, may affect only certain hSOD1 mutants, these findings contribute to our understanding of the potential difference in the molecular pathways by which different hSOD1 mutants generate disease.http://www.sciencedirect.com/science/article/pii/S0969996111001422Amyotrophic lateral sclerosisGlutathioneGCLMMitochondria
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	Marcelo R. Vargas Delinda A. Johnson Jeffrey A. Johnson
spellingShingle	Marcelo R. Vargas Delinda A. Johnson Jeffrey A. Johnson Decreased glutathione accelerates neurological deficit and mitochondrial pathology in familial ALS-linked hSOD1G93A mice model Neurobiology of Disease Amyotrophic lateral sclerosis Glutathione GCLM Mitochondria
author_facet	Marcelo R. Vargas Delinda A. Johnson Jeffrey A. Johnson
author_sort	Marcelo R. Vargas
title	Decreased glutathione accelerates neurological deficit and mitochondrial pathology in familial ALS-linked hSOD1G93A mice model
title_short	Decreased glutathione accelerates neurological deficit and mitochondrial pathology in familial ALS-linked hSOD1G93A mice model
title_full	Decreased glutathione accelerates neurological deficit and mitochondrial pathology in familial ALS-linked hSOD1G93A mice model
title_fullStr	Decreased glutathione accelerates neurological deficit and mitochondrial pathology in familial ALS-linked hSOD1G93A mice model
title_full_unstemmed	Decreased glutathione accelerates neurological deficit and mitochondrial pathology in familial ALS-linked hSOD1G93A mice model
title_sort	decreased glutathione accelerates neurological deficit and mitochondrial pathology in familial als-linked hsod1g93a mice model
publisher	Elsevier
series	Neurobiology of Disease
issn	1095-953X
publishDate	2011-09-01
description	Dominant mutations in Cu/Zn-superoxide dismutase (SOD1) cause familial forms of amyotrophic lateral sclerosis (ALS), a fatal disorder characterized by the progressive loss of motor neurons. To investigate the role of antioxidant defenses in ALS we used knockout mice for the glutamate-cysteine ligase modifier subunit (GCLM−/−), which have a 70–80% reduction in total glutathione. Although GCLM(−/−) mice are viable and fertile, the life span of GCLM(−/−)/hSOD1G93A mice decreased in 55% when compared to GCLM(+/+)/hSOD1G93A mice. Decreased life span in GCLM(−/−)/hSOD1G93A mice was associated to increased oxidative stress, aggravated mitochondrial pathology and increased association of hSOD1 with the mitochondria. Interestingly, when the GCLM(−/−) animals were mated with a different ALS-model which overexpress the experimental mutation hSOD1H46R/H48Q, no effect was observed in survival of GCLM(−/−)/hSOD1H46R/H48Q mice; and little or no mitochondrial pathology was observed. Since a specific disease modifier, such as glutathione deficiency, may affect only certain hSOD1 mutants, these findings contribute to our understanding of the potential difference in the molecular pathways by which different hSOD1 mutants generate disease.
topic	Amyotrophic lateral sclerosis Glutathione GCLM Mitochondria
url	http://www.sciencedirect.com/science/article/pii/S0969996111001422
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Decreased glutathione accelerates neurological deficit and mitochondrial pathology in familial ALS-linked hSOD1G93A mice model

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