)| PMID |
10930589 ( ) |
|---|---|
| Title | Increased reactive oxygen species in familial amyotrophic lateral sclerosis with mutations in SOD1. |
| Abstract | Amyotrophic lateral sclerosis (ALS) is a paralytic disorder characterized by degeneration of large motor neurons of the brain and spinal cord. A subset of ALS is inherited (familial ALS, FALS) and is associated with more than 70 different mutations in the SOD1 gene. Here we report that lymphoblast cell lines derived from FALS patients with 16 different mutations in SOD1 gene exhibit significant increase of intracellular reactive oxygen species (ROS) compared with sporadic ALS (SALS) and normal controls (spouses of ALS patients). The ROS generation did not correlate with SOD1 activity. Further, cells incubated with vitamin C, catalase or the flavinoid quercetin significantly reduced ROS in all groups. The catalase inhibitor 3-amino-1,2,4-triazole resulted in a ten-fold increase of ROS in all groups. Neither L-nitroarginine, a nitric oxide synthase inhibitor or vitamin E altered the ROS levels. Thus, these studies suggest that hydrogen peroxide (H(2)O(2)) is a major ROS elevated in FALS lymphoblasts and it may contribute to the degeneration of susceptible cells. Further, we postulate a mechanism by which increased H(2)O(2) could be generated by mutant SOD1. 13-715, 303 East Chicago Avenue, 60611, Chicago, IL, USA. |
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)) | 53 | SOD1 | SOD | superoxide dismutase | |
| 1516 | CAT | catalase | 7 | catalase | |
| 7872 | NOS1 | nitric oxide synthase 1 (neuronal) | 4 | NOS | |
| 7873 | NOS2A | nitric oxide synthase 2A (inducible, hepatocytes) | 2 | nitric oxide synthase | |
| 11180 | SOD2 | superoxide dismutase 2, mitochondrial | 1 | MnSOD | |
Targets by SciMiner Full list
| HUGO ID | Symbol | Name | ActualStr | Score | FlankingText |
|---|---|---|---|---|---|
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.1 | is associated with more than 70 different mutations in the SOD1 gene |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.1 | lines derived from FALS patients with 16 different mutations in SOD1 gene exhibit significant increase of intracellular reactive oxygen species (ROS) |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.1 | The ROS generation did not correlate with SOD1 activity |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.1 | increased H 2 O 2 could be generated by mutant SOD1 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.1 | in the gene for cytosolic Cu Zn superoxide dismutase ( SOD1 CuZnSOD 1 and 2 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.1 | SOD1 functions as a homodimeric enzyme that is widely expressed and |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.1 | The mechanisms by which SOD1 mutations cause selective motor neuron degeneration is not clearly understood |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.1 | However SOD1 activity in red blood cells of most SOD1 mutant heterozygotes |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.1 | However SOD1 activity in red blood cells of most SOD1 mutant heterozygotes is reduced |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.1 | be less than 50% in some cases suggesting that mutant SOD1 may affect the activity of the wildtype enzyme 2 3 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.1 | Evidence from SOD1 transgenic mice and SOD1 knockout mice suggests that reduced dismutase |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.1 | Evidence from SOD1 transgenic mice and SOD1 knockout mice suggests that reduced dismutase activity is not the |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.1 | Decreased SOD1 activity in ALS patients would be expected to lead to |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.1 | Mutant SOD1 was shown to have increased peroxidase activity over wildtype SOD1 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.1 | SOD1 was shown to have increased peroxidase activity over wildtype SOD1 in vitro |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.1 | Thus mutant SOD1 may produce more free radicals than wild SOD1 7 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.1 | Thus mutant SOD1 may produce more free radicals than wild SOD1 7 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.1 | show any difference in peroxidase activity of mutant and wildtype SOD1 8 and 9 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.1 | was shown this discrepancy was due to different preparations of SOD1 proteins and experimental conditions 8 and 9 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.1 | (ROS) ROS in lymphoblast cell lines derived from patients with SOD1 linked FALS sporadic ALS and normal controls (spouses spouses of |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.1 | were similar in all groups despite a 45% decrease in SOD1 activity in FALS mutants |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD | 2.2 | SOD assay |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD | 2.2 | Total SOD activity was determined by its ability to catalyze the disproportionation |
| 11180 | SOD2 | superoxide dismutase 2, mitochondrial | MnSOD | 1.9 | Cyanide (3 3 mM was used to distinguish between resistant MnSOD and the sensitive CuZnSOD |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.1 | No significant correlation was observed between relative C-DCF fluorescence and SOD1 activity in all groups at resting levels |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.1 | with menadione showed an inverse correlation of C-DCF fluorescence with SOD1 activity ( r =0.6 P _amp_#x3c 0.001 ( Table 1 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.1 | is unlikely to be increased in FALS cells despite reduced SOD1 activity |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.1 | Previous studies have shown that SOD1 is inhibited by a number of metal chelating agents e.g |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.1 | Reaction of SOD1 with DDC requires two molecule of DDC (i) i one |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.1 | (i) i one molecule interacts with the copper center of SOD1 with retention of activity (ii) ii while a second molecule |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.1 | This suggests the interaction of DDC with mutant SOD1 may be altered and that wildtype SOD1 contributes approximately 30_amp_#x2013 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.1 | DDC with mutant SOD1 may be altered and that wildtype SOD1 contributes approximately 30_amp_#x2013 50% of C-DCF fluorescence in resting cells |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.1 | SOD1 is a major source of H 2 O 2 in |
| 7872 | NOS1 | nitric oxide synthase 1 (neuronal) | NOS | 1.2 | ascorbic acid -nitroarginine an inhibitor of nitric oxide synthase (NOS) NOS 27 did not affect the C-DCF fluorescence in resting cells |
| 7872 | NOS1 | nitric oxide synthase 1 (neuronal) | NOS | 1.2 | all groups with -nitroarginine treatment suggesting a protective role of NOS in menadione stressed cells |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.1 | Since mutations in SOD1 are associated with FALS and activity of SOD1 is decreased |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.1 | mutations in SOD1 are associated with FALS and activity of SOD1 is decreased (primarily primarily due to decreased half life of |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.1 | decreased (primarily primarily due to decreased half life of mutant SOD1 we investigated whether this would lead to increased free radical |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.1 | O 2 ._amp_#x2212 is cleared very quickly from cells by SOD1 28 even when SOD1 is reduced by 50% |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.1 | cleared very quickly from cells by SOD1 28 even when SOD1 is reduced by 50% |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.1 | Our hypothesis is that copper in mutant SOD1 is available to O 2 ._amp_#x2212 only or mostly in |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.1 | it is reported to have a greater interaction with mutant SOD1 than with wildtype SOD1 7 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.1 | have a greater interaction with mutant SOD1 than with wildtype SOD1 7 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.1 | hypothesis of increased H 2 O 2 generation by mutant SOD1 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.1 | has shown that DDC reacts with Cu(II) Cu II of SOD1 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.1 | The reaction of DDC with SOD1 was shown to occur in two phases |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.1 | a modest concentration of DDC (0.1_amp_#x2013;1.0 0.1_amp_#x2013 1.0 mM and SOD1 retains its full dismutase activity 19 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.1 | Phase 2 involves displacement of Cu(II) Cu II from SOD1 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.1 | Cu(II) Cu II polymerize into colloidal particles stabilized by unfolded SOD1 protein subunits |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.1 | equal to 10 mM and leads to a loss of SOD1 dismutase activity 19 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.1 | The contribution of SOD1 to C-DCF fluorescence in our studies was demonstrated by using |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.1 | Fig 3A and B suggests that hydrogen peroxide generated by SOD1 was indeed involved in the oxidation of C-DCDHF |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.1 | cells suggesting either altered interaction or modified stoichiometry between mutant SOD1 and DDC |
| 7872 | NOS1 | nitric oxide synthase 1 (neuronal) | NOS | 1.2 | vitamin C and the flavinoid quercetin but not inhibitor of NOS supports the conclusion that C-DCDHF was oxidized by H 2 |
| 7872 | NOS1 | nitric oxide synthase 1 (neuronal) | NOS | 1.2 | biological membranes against lipid peroxidation and -nitroarginine (inhibitor inhibitor of NOS showed no effect in ROS levels of all groups tested |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.1 | 2 O 2 damage due to increased concentrations of mutant SOD1 in these cells |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 5.1 | Such an accumulation of mutant SOD1 has been reported in FALS spinal cords 33 and could |
| 1516 | CAT | catalase | catalase | 1.0 | further cells incubated with vitamin c catalase or the flavinoid quercetin significantly reduced ros in all groups. |
| 1516 | CAT | catalase | catalase | 1.0 | the catalase inhibitor 3 amino 1 2 4 triazole resulted in a ten fold increase of ros in all groups. |
| 7873 | NOS2A | nitric oxide synthase 2A (inducible, hepatocytes) | nitric oxide synthase | 1.0 | neither nitroarginine a nitric oxide synthase inhibitor or vitamin e altered the ros levels. |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | superoxide dismutase | 1.0 | about 2% of als cases are associated with missense mutations in the gene for cytosolic cu zn superoxide dismutase sod1 cuznsod [ 1 and 2 ]. |
| 1516 | CAT | catalase | catalase | 1.0 | lactate dehydrogenase ldh activity was used to calculate the specific fluorescence. nitroarginine aldrich catalase boehringer mannheim and other chemicals sigma studied were added 15 min before loading of the cells with c dcdhf da am table 1 . |
| 1516 | CAT | catalase | catalase | 1.0 | sod1 is a major source of h 2 o 2 in cells [ 20 ] and catalase and glutathione peroxidase are the primary enzymes responsible for decomposition of h 2 o 2 [ 21 ]. |
| 1516 | CAT | catalase | catalase | 1.0 | catalase reduced the c dcf fluorescence in resting or menadione stimulated cells in all three groups of cells tested. |
| 1516 | CAT | catalase | catalase | 1.0 | however the reduction was more pronounced in menadione stimulated cells. 3 amino 1 2 4 triazole 3 at an inhibitor of catalase [ 22 and 23 ] increased the c dcf fluorescence of all three types of cells. |
| 7873 | NOS2A | nitric oxide synthase 2A (inducible, hepatocytes) | nitric oxide synthase | 1.0 | quercetin a bio flavonoid molecule with antioxidant properties [ 26 ] showed effects similar to ascorbic acid. nitroarginine an inhibitor of nitric oxide synthase nos [ 27 ] did not affect the c dcf fluorescence in resting cells of any group. |
| 1516 | CAT | catalase | catalase | 1.0 | reduction of c dcf fluorescence by catalase and other antioxidants vitamin c and the flavinoid quercetin but not inhibitor of nos supports the conclusion that c dcdhf was oxidized by h 2 o 2 table 2 . |