Document Information

PMID 12901835  (  )
Title Mitochondrial dysfunction due to mutant copper/zinc superoxide dismutase associated with amyotrophic lateral sclerosis is reversed by N-acetylcysteine.
Abstract We report that the expression of mutant G93A copper/zinc superoxide dismutase (SOD1), associated with familial amyotrophic lateral sclerosis, specifically causes a decrease in MTT reduction rate and ATP levels and an increase in both cytosolic and mitochondrial reactive oxygen species (ROS) production in human neuroblastoma SH-SY5Y cells compared to cells overexpressing wild-type SOD1 and untransfected cells. Exposure to N-acetylcysteine lowers ROS production and returns mitochondrial functional assays to control levels. No large aggregates of human SOD1 are detectable under basal growth conditions in any of the investigated cell lines. After proteasome activity inhibition, SOD1 aggregates can be detected exclusively in G93A-SOD1 cells, even though they do not per se enhance cell death compared to control cell lines. Our findings indicate that mitochondrial homeostasis is affected by mutant SOD1-generated ROS independently from the formation of aggregates and that this alteration is reversed by antioxidants. Milano-Bicocca, San Gerardo Hospital, via Donizetti, 106, 20052, Monza (MI), Italy.

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Targets by SciMiner Summary

HUGO ID Symbol Target Name #Occur ActualStr
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))41SOD1-generated | SOD1-positive | SOD1-linked | SOD1s | superoxide dismutase | sod1 |
1504CASP3caspase 3, apoptosis-related cysteine peptidase2caspase 3 |
1613CCScopper chaperone for superoxide dismutase2CCS |
7808NGFnerve growth factor (beta polypeptide)2nerve growth factor | NGF |
31395COX8Bcytochrome c oxidase, subunit 8B pseudogene1cytochrome c oxidase |
7688NDUFA5NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 5, 13kDa1ubiquinone reductase |

 

Targets by SciMiner Full list

HUGO ID Symbol Name ActualStr Score FlankingText
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD12.4expression of mutant G93A copper/zinc copper zinc superoxide dismutase (SOD1), SOD1 associated with familial amyotrophic lateral sclerosis specifically causes a decrease
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD12.4in human neuroblastoma SH-SY5Y cells compared to cells overexpressing wild-type SOD1 and untransfected cells
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD12.4No large aggregates of human SOD1 are detectable under basal growth conditions in any of the
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD1-generated1.9Our findings indicate that mitochondrial homeostasis is affected by mutant SOD1-generated ROS independently from the formation of aggregates and that this
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD12.4coding for the antioxidant enzyme Cu Zn superoxide dismutase (SOD1) SOD1 Siddique et al 1991 Deng et al 1993 and Rosen
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD12.4SOD1 typically has an antioxidant function because it removes the superoxide
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))sod12.4However mutations in sod1 gene do not cause FALS through simple loss of dismutating
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD1s1.9et al 1993 several lines of evidence indicate that mutant SOD1s are responsible for the death of motor neurons through the
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD12.4be responsible for the enhancement of the peroxidative activity of SOD1 as independently reported by two groups Wiedau-Pazos et al 1996
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD1s1.9The second hypothesis relies on the observation that misfolded mutant SOD1s might release their metal ions (copper copper and zinc and
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD12.4In particular decrease of the copper-buffering properties of SOD1 Steinkuhler et al 1991 could result in an increase of
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD1s1.9It is not clear at present whether misfolded SOD1s would also bind copper ions and mediate increase in oxidative
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD12.4neuron disease with mice devoid of the Copper Chaperone for SOD1 (CCS CCS _amp_#x2212;/_amp_#x2212;) _amp_#x2212 _amp_#x2212 does not rescue the phenotype
1613CCScopper chaperone for superoxide dismutaseCCS1.2with mice devoid of the Copper Chaperone for SOD1 (CCS CCS _amp_#x2212;/_amp_#x2212;) _amp_#x2212 _amp_#x2212 does not rescue the phenotype Subramaniam et
1613CCScopper chaperone for superoxide dismutaseCCS1.2However although it is most probable that CCS is not directly involved in ALS mishandling of copper is
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD12.4as the major culprit in oxidative stress induced by mutant SOD1 Bush 2002
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD12.4The recent demonstration that a substantial amount of SOD1 (previously previously thought of as being exclusively a cytosolic enzyme
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD1-linked1.9reductase defects have been shown both in postmortem brains from SOD1-linked FALS patients Browne et al 1998 and in skeletal muscle
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD12.4spinal motor neurons of transgenic mice carrying G93A mutant human SOD1 Warita et al 2001
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD12.4by site-directed mutagenesis of the cDNA coding for that mutant SOD1 cloning in expression vectors and transfection of parental human neuroblastoma
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD12.4using the Immun-blot kit from Bio-Rad with a polyclonal antihuman SOD1 antibody Steinkuhler et al 1991
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD12.4for 2 h at 37_amp_#xb0 C with a monoclonal antimouse SOD1 antibody (Sigma) Sigma 1 300 and for 2 h at
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD12.40.05 in line with the well-known protective role of wild-type SOD1 overexpression against free radicals
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD12.4Aggregation of mutant SOD1
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD12.4It has been suggested that aggregation of misfolded mutant SOD1 contributes to neurodegeneration in FALS
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD12.4However it is still debated whether SOD1 aggregates represent a cause a correlate or a consequence of
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD12.4In all of our lines no large aggregates of human SOD1 are detectable after immunostaining in basal growth conditions ( Fig
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD12.4localized in the cytoplasm and roughly paralleled the level of SOD1 expression being more intense in transfected cells than in control
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD1-positive1.9specifically inhibit the proteasome activity with lactacystin for 16 h SOD1-positive aggregates localize in the cytoplasm of 30_amp_#x2013 40% cells expressing
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD1s1.9localize in the cytoplasm of 30_amp_#x2013 40% cells expressing mutant SOD1s but not in control cells
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD12.4is paralleled by the appearance of an insoluble fraction containing SOD1 in extracts from cells expressing mutant SOD1 as seen in
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD12.4insoluble fraction containing SOD1 in extracts from cells expressing mutant SOD1 as seen in Western blot experiments where detergent-soluble and -insoluble
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD12.4to demonstrate that human neuroblastoma SH-SY5Y cell lines carrying G93A SOD1 mutation possess remarkable biochemical abnormalities compared to control cells such
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD12.4This provides evidence that G93A SOD1 mutation acts as a remarkable source of intracellular oxidative stress
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD12.4and mitochondrial ultrastructural abnormalities were found in animal models carrying SOD1 mutations Wong et al 1995
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD12.4be a direct consequence of the pro-oxidant activity of mutant SOD1 indeed the use of NAC promptly reverts both increase in
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD12.4survival and motor performance in transgenic mice with a G93A SOD1 mutation Andreassen et al 2000
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD12.4When we specifically inhibit the proteasome activity insoluble SOD1 aggregates localize in the cytoplasm of cells expressing mutant SOD1s
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD1s1.9SOD1 aggregates localize in the cytoplasm of cells expressing mutant SOD1s but not in control cells
7808NGFnerve growth factor (beta polypeptide)NGF1.2is not causative of death in nerve growth factor (NGF)-differentiated NGF -differentiated PC12 cells transfected with mutant SOD1s (SODMT, SODMT V148G
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD1s1.9growth factor (NGF)-differentiated NGF -differentiated PC12 cells transfected with mutant SOD1s (SODMT, SODMT V148G or A4V
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD12.4survey on the properties of a large number of mutant SOD1 in vitro Hayward et al 2002 and Rodriguez et al
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))superoxide dismutase1.0we report that the expression of mutant g93a copper/zinc superoxide dismutase sod1 associated with familial amyotrophic lateral sclerosis specifically causes a decrease in mtt reduction rate and atp levels and an increase in both cytosolic and mitochondrial reactive oxygen spe
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))superoxide dismutase1.0in the early 1990s it has been demonstrated that about 20% of familial als fals patients possess point mutations in the gene coding for the antioxidant enzyme cu zn superoxide dismutase sod1 [ siddique et al 1991 deng et al 1993 and rosen et al 1993 ].
31395COX8Bcytochrome c oxidase, subunit 8B pseudogenecytochrome c oxidase1.0decreased activity of cytochrome c oxidase was demonstrated in spinal cord motor neurons [ borthwick et al 1999 ] and lymphocytes [ curti et al 1996 ] from sals patients.
7688NDUFA5NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 5, 13kDaubiquinone reductase1.0nadh ubiquinone reductase defects have been shown both in postmortem brains from sod1 linked fals patients [ browne et al 1998 ] and in skeletal muscle from sals patients [ vielhaber et al 1999 ].
1504CASP3caspase 3, apoptosis-related cysteine peptidasecaspase 31.0caspase 3 activity apoalert caspase 3 colorimetric assay kit clontech palo alto usa
1504CASP3caspase 3, apoptosis-related cysteine peptidasecaspase 31.0neither caspase 3 activation fig 1b nor the number of condensed nuclei fig 1c_amp_#x2013;e was found to be significantly increased in g93a mutant cells indicating that no significant spontaneous apoptotic tendency was
7808NGFnerve growth factor (beta polypeptide)nerve growth factor1.0this is in line with the recent report [ lee et al 2002 ] that aggregation of fals sod1 is not causative of death in nerve growth factor ngf differentiated pc12 cells transfected with mutant sod1s sodmt v148g or a4v .