)| PMID |
15812313 ( ) |
|---|---|
| Title | Pyruvate protects motor neurons expressing mutant superoxide dismutase 1 against copper toxicity. |
| Abstract | Mutations in the copper/zinc superoxide dismutase (SOD1) gene are known to be responsible for familial amyotrophic lateral sclerosis. Alteration of metal binding properties of mutant SOD1 has been proposed to play a role in the pathogenesis of amyotrophic lateral sclerosis. We investigated the toxic effects of excess extracellular copper on motor neuronal cells expressing human mutant SOD1 (G93A), and evaluated the neuroprotective effects of energy metabolism intermediates or cofactors. Motoneuron-neuroblastoma hybrid (VSC 4.1) cells expressing mutant SOD1, when treated with copper chloride, showed reduced viability and increased levels of endogenous peroxides. Moreover, this copper-induced toxicity was attenuated by a free radical scavenger, a caspase inhibitor, or a calpain inhibitor. Of the energy metabolism intermediates examined, pyruvate significantly reduced the death and production of reactive oxygen species in cells expressing mutant SOD1. Our data suggest that pyruvate could be of therapeutic value in some forms of familial amyotrophic lateral sclerosis. Clinical Research Institute of Seoul National University Hospital, Chongnoku, Seoul 110-744, Korea. |
NOTE: Color highlight is limited to the abstract and SciMiner text-mining mode. If you see much more identified targets below from "Targets by SciMiner Summary" and "Targets by SciMiner Full list", they may have been identified from the full text.
Targets by SciMiner Summary
| HUGO ID | Symbol | Target Name | #Occur | ActualStr |
|---|---|---|---|---|
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | 40 | SOD1 | SOD | superoxide dismutase | |
| 1515 | CAST | calpastatin | 2 | calpain inhibitor | |
| 8808 | PDHB | pyruvate dehydrogenase (lipoamide) beta | 2 | pyruvate dehydrogenase | |
| 8806 | PDHA1 | pyruvate dehydrogenase (lipoamide) alpha 1 | 2 | PDH | |
| 2295 | CP | ceruloplasmin (ferroxidase) | 1 | ceruloplasmin | |
| 31395 | COX8B | cytochrome c oxidase, subunit 8B pseudogene | 1 | cytochrome c oxidase | |
Targets by SciMiner Full list
| HUGO ID | Symbol | Name | ActualStr | Score | FlankingText |
|---|---|---|---|---|---|
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 3.2 | Mutations in the copper_amp_#47 zinc superoxide dismutase (SOD1) SOD1 gene are known to be responsible for familial amyotrophic lateral |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 3.2 | Alteration of metal binding properties of mutant SOD1 has been proposed to play a role in the pathogenesis |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 3.2 | excess extracellular copper on motor neuronal cells expressing human mutant SOD1 (G93A), G93A and evaluated the neuroprotective effects of energy metabolism |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 3.2 | Motoneuron-neuroblastoma hybrid (VSC VSC 4.1 cells expressing mutant SOD1 when treated with copper chloride showed reduced viability and increased |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 3.2 | and production of reactive oxygen species in cells expressing mutant SOD1 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 3.2 | The mutation in the copper_amp_#47 zinc superoxide dismutase (SOD1) SOD1 gene is known to be associated with the familial ALS |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 3.2 | ALS (FALS) FALS because of some undefined property of mutant SOD1 protein _amp_#91 1 _amp_#93 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 3.2 | SOD1 mutations cause the disease through a gain of function or |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD | 2.2 | of function or by enhancing an unknown nondismutase activity of SOD _amp_#91 2 _amp_#93 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 3.2 | Several pathophysiological mechanisms linking the SOD1 mutation with FALS have been proposed |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 3.2 | They include a failure to fold or degrade mutant SOD1 the formation of free radicals the susceptibility of mutant SOD1 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 3.2 | SOD1 the formation of free radicals the susceptibility of mutant SOD1 to disulfide reduction and the release of free copper _amp_#91 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 3.2 | hypotheses have been proposed concerning the metal binding properties of SOD1 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 3.2 | (NO), NO reacts with the Cu 2_amp_#43 ion of mutant SOD1 to produce nitronium ions which then nitrate proteins and induce |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 3.2 | and Yim et al _amp_#91 7 _amp_#93 reported that mutant SOD1 has higher peroxidase activity than the wild type (WT), WT |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 3.2 | et al _amp_#91 8 _amp_#93 proposed that the FALS-associated mutant SOD1 failed to bind or shield Cu 2_amp_#43 as effectively as |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 3.2 | by a mechanism involving the altered copper-dependent activity of mutant SOD1 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 3.2 | If an altered copper binding capacity by SOD1 protein causes a toxic gain of function neurons with SOD1 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 3.2 | SOD1 protein causes a toxic gain of function neurons with SOD1 mutations are likely to be more vulnerable to excess copper |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 3.2 | Furthermore mutant SOD1 mice have significant elevations in brain or spinal cord copper |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 3.2 | elevation of copper is probably copper bound to the over-expressed SOD1 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 3.2 | Therefore SOD1 mutant neurons would be more vulnerable to an exogenous load |
| 8806 | PDHA1 | pyruvate dehydrogenase (lipoamide) alpha 1 | PDH | 0.3 | formation of 4-hydroxy nonenal and it inhibits pyruvate dehydrogenase (PDH) PDH by covalently modifying the lipoic acid moiety of the enzyme |
| 8806 | PDHA1 | pyruvate dehydrogenase (lipoamide) alpha 1 | PDH | 0.3 | intermediate of energy metabolism thiamine and lipoic acid cofactors of PDH were tested to have neuroprotective effects against copper overload |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 3.2 | WT or mutant (G93A) G93A human SOD1 cDNA (a a gift from Dr Lawrence J Hayward University |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 3.2 | USA with pcDNA3.1 vector containing cDNA encoding WT or G93A SOD1 and then selected using geneticin (G418 G418 sulfate Gibco |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 3.2 | or pooled colonies were used for experiments after determining human SOD1 expression by Western blot and immunohistochemical staining |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 3.2 | The cells expressing human SOD1 were cultured in a medium containing geneticin at 200 microg_amp_#47 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 3.2 | (Cu Cu 2_amp_#43 on the death of cells expressing mutant SOD1 the cells were treated with various agents prior to exposing |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 3.2 | VSC 4.1 cells expressing human WT or mutant SOD1 (G93A) G93A were exposed to increasing concentrations of Cu 2_amp_#43 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 3.2 | treatment (250 250 microM in cells expressing WT or mutant SOD1 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 3.2 | In cells expressing WT SOD1 Cu 2_amp_#43 -induced cell death was not affected by trolox |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 3.2 | attenuate Cu 2_amp_#43 -induced neuronal death in cells expressing mutant SOD1 ( Fig 2a |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 3.2 | concentrations reduce the survival of VSC 4.1 cells expressing human SOD1 mutated at G93A and that pyruvate protects these cells from |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 3.2 | functioning of several enzymes including cytochrome c oxidase ceruloplasmin and SOD1 _amp_#91 13 _amp_#93 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 3.2 | 2_amp_#43 reduces the viability of VSC 4.1 cells expressing mutant SOD1 (G93A) G93A |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 3.2 | through this property in VSC 4.1 cells harboring the G93A SOD1 mutation |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 3.2 | free radical scavenging action in VSC 4.1 cells expressing mutant SOD1 (G93A) G93A |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 3.2 | found to be toxic to motor neuronal cells expressing mutant SOD1 and pyruvate attenuated this Cu 2_amp_#43 -induced neuronal death |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 3.2 | and energy metabolism enhancing actions in motor neurons harboring the SOD1 mutation |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | superoxide dismutase | 1.0 | mutations in the copper_amp_#47;zinc superoxide dismutase sod1 gene are known to be responsible for familial amyotrophic lateral sclerosis. |
| 1515 | CAST | calpastatin | calpain inhibitor | 1.0 | moreover this copper induced toxicity was attenuated by a free radical scavenger a caspase inhibitor or a calpain inhibitor. |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | superoxide dismutase | 1.0 | the mutation in the copper_amp_#47;zinc superoxide dismutase sod1 gene is known to be associated with the familial als fals because of some undefined property of mutant sod1 protein _amp_#91; 1 _amp_#93;. |
| 8808 | PDHB | pyruvate dehydrogenase (lipoamide) beta | pyruvate dehydrogenase | 1.0 | copper overload induces lipid peroxidation marked by the formation of 4 hydroxy nonenal and it inhibits pyruvate dehydrogenase pdh by covalently modifying the lipoic acid moiety of the enzyme _amp_#91; 10 _amp_#93;. |
| 1515 | CAST | calpastatin | calpain inhibitor | 1.0 | of cells expressing mutant sod1 the cells were treated with various agents prior to exposing the cells to cu 2_amp_#43; namely enzyme inhibitors _amp_#91;z vad fmk a pan caspase inhibitor calpeptin a calpain inhibitor _amp_#93; intermediates of energy metabolism or cofactors of mitochondrial enzymes pyruvate thiamine lipoic acid alternate energy substrates lactate oxaloacetate [alpha] ketoglutarate free radical sc |
| 2295 | CP | ceruloplasmin (ferroxidase) | ceruloplasmin | 1.0 | copper is an essential trace metal and is required for the proper functioning of several enzymes including cytochrome c oxidase ceruloplasmin and sod1 _amp_#91; 13 _amp_#93;. |
| 31395 | COX8B | cytochrome c oxidase, subunit 8B pseudogene | cytochrome c oxidase | 1.0 | copper is an essential trace metal and is required for the proper functioning of several enzymes including cytochrome c oxidase ceruloplasmin and sod1 _amp_#91; 13 _amp_#93;. |
| 8808 | PDHB | pyruvate dehydrogenase (lipoamide) beta | pyruvate dehydrogenase | 1.0 | this cu 2_amp_#43; neurotoxicity was attenuated by the pyruvate dehydrogenase cofactors thiamine or dihydrolipoic acid. |