)| PMID |
18219386 ( ) |
|---|---|
| Title | Revisiting oxidative damage in ALS: microglia, Nox, and mutant SOD1. |
| Abstract | Mutation in superoxide dismutase-1 (SOD1) causes the inherited degenerative neurological disease familial amyotrophic lateral sclerosis (ALS), a non-cell-autonomous disease: mutant SOD1 synthesis in motor neurons and microglia drives disease onset and progression, respectively. In this issue of the JCI, Harraz and colleagues demonstrate that SOD1 mutants expressed in human cell lines directly stimulate NADPH oxidase (Nox) by binding to Rac1, resulting in overproduction of damaging ROS (see the related article beginning on page 659). Diminishing ROS by treatment with the microglial Nox inhibitor apocynin or by elimination of Nox extends survival in ALS mice, reviving the proposal that ROS mediate ALS pathogenesis, but with a new twist: it's ROS produced by microglia. Department of Neuroscience, UCSD, La Jolla, California 92030, 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)) | 61 | SOD1 | SOD1-interacting | |
| 2578 | CYBB | cytochrome b-245, beta polypeptide (chronic granulomatous disease) | 29 | CGD | Nox2 | NOX2 | gp91 phox | |
| 9801 | RAC1 | ras-related C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1) | 14 | Rac1 | |
| 7661 | NCF2 | neutrophil cytosolic factor 2 (65kDa, chronic granulomatous disease, autosomal 2) | 9 | chronic granulomatous disease | p67 phox | |
| 7660 | NCF1 | neutrophil cytosolic factor 1, (chronic granulomatous disease, autosomal 1) | 7 | p47 | |
| 391 | AKT1 | v-akt murine thymoma viral oncogene homolog 1 | 6 | Rac | |
| 14874 | NOX5 | NADPH oxidase, EF-hand calcium binding domain 5 | 6 | Nox5 | nadph oxidase | NOX5 | |
| 7889 | NOX1 | NADPH oxidase 1 | 5 | Nox1 | |
| 2577 | CYBA | cytochrome b-245, alpha polypeptide | 4 | p22 phox | |
| 7662 | NCF4 | neutrophil cytosolic factor 4, 40kDa | 3 | p40 | |
| 13273 | DUOX2 | dual oxidase 2 | 2 | DUOX2 | Duox2 | |
| 7891 | NOX4 | NADPH oxidase 4 | 2 | Nox4 | |
| 620 | APP | amyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease) | 1 | amyloid | |
| 670 | RHOD | ras homolog gene family, member D | 1 | Rho | |
| 1613 | CCS | copper chaperone for superoxide dismutase | 1 | CCS | |
| 3062 | DUOX1 | dual oxidase 1 | 1 | Duox1 | |
Targets by SciMiner Full list
| HUGO ID | Symbol | Name | ActualStr | Score | FlankingText |
|---|---|---|---|---|---|
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.5 | Abstract Mutation in superoxide dismutase_amp_#x02013 1 (SOD1) SOD1 causes the inherited degenerative neurological disease familial amyotrophic lateral sclerosis |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.5 | amyotrophic lateral sclerosis (ALS), ALS a non_amp_#x02013 cell-autonomous disease mutant SOD1 synthesis in motor neurons and microglia drives disease onset and |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.5 | this issue of the JCI Harraz and colleagues demonstrate that SOD1 mutants expressed in human cell lines directly stimulate NADPH oxidase |
| 9801 | RAC1 | ras-related C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1) | Rac1 | 1.0 | lines directly stimulate NADPH oxidase (Nox) Nox by binding to Rac1 resulting in overproduction of damaging ROS (see see the related |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.5 | lateral sclerosis Nox NADPH oxidase O 2 _amp_#x02022 _amp_#x02013 superoxide SOD1 superoxide dismutase_amp_#x02013 1 |
| 2578 | CYBB | cytochrome b-245, beta polypeptide (chronic granulomatous disease) | Nox2 | 3.5 | Figure 1 Production of ROS by microglial Nox2 during inflammation is amplified by mutant SOD1 binding to Rac1 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.5 | ROS by microglial Nox2 during inflammation is amplified by mutant SOD1 binding to Rac1 in ALS |
| 9801 | RAC1 | ras-related C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1) | Rac1 | 1.0 | Nox2 during inflammation is amplified by mutant SOD1 binding to Rac1 in ALS |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.5 | cases of disease mutations in the superoxide dismutase_amp_#x02013 1 ( SOD1 gene are the most frequently identified |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.5 | SOD1 catalyzes the conversion of superoxide (O2 O2 _amp_#x02022 _amp_#x02013 to |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.5 | Indeed SOD1 mimetics have been reported to slow disease progression when administered |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.5 | more compelling are data obtained by selective silencing of mutant SOD1 synthesis by microglia ( 11 or replacement of the mutant |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.5 | Both approaches demonstrate that mutant SOD1 synthesis in inflammatory cells of the CNS directly accelerates the |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.5 | By crossing mice expressing the SOD1 G93A mutant with mice lacking a catalytic subunit of Nox |
| 7889 | NOX1 | NADPH oxidase 1 | Nox1 | 1.2 | of Nox (through through deletion of the gene encoding either Nox1 or Nox2 an increase in survival was seen with Nox2 |
| 2578 | CYBB | cytochrome b-245, beta polypeptide (chronic granulomatous disease) | Nox2 | 3.5 | (through through deletion of the gene encoding either Nox1 or Nox2 an increase in survival was seen with Nox2 deletion proving |
| 2578 | CYBB | cytochrome b-245, beta polypeptide (chronic granulomatous disease) | Nox2 | 3.5 | Nox1 or Nox2 an increase in survival was seen with Nox2 deletion proving to be of greater benefit than Nox1 deletion |
| 7889 | NOX1 | NADPH oxidase 1 | Nox1 | 1.2 | with Nox2 deletion proving to be of greater benefit than Nox1 deletion ( 14 |
| 2578 | CYBB | cytochrome b-245, beta polypeptide (chronic granulomatous disease) | Nox2 | 3.5 | Consistent with progressive microglial activation during disease Nox2 expression was upregulated in SOD1 G93A mice ( 13 14 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.5 | progressive microglial activation during disease Nox2 expression was upregulated in SOD1 G93A mice ( 13 14 and sporadic ALS patients ( |
| 14874 | NOX5 | NADPH oxidase, EF-hand calcium binding domain 5 | Nox5 | 0.9 | The Nox family is composed of 7 members Nox1_amp_#x02013 Nox5 Duox1 and Duox2 are distributed in a variety of tissues |
| 3062 | DUOX1 | dual oxidase 1 | Duox1 | 0.3 | The Nox family is composed of 7 members Nox1_amp_#x02013 Nox5 Duox1 and Duox2 are distributed in a variety of tissues |
| 13273 | DUOX2 | dual oxidase 2 | DUOX2 | 0.3 | The Nox family is composed of 7 members Nox1_amp_#x02013 Nox5 Duox1 and Duox2 are distributed in a variety of tissues |
| 13273 | DUOX2 | dual oxidase 2 | Duox2 | 0.3 | family is composed of 7 members Nox1_amp_#x02013 Nox5 Duox1 and Duox2 are distributed in a variety of tissues |
| 2578 | CYBB | cytochrome b-245, beta polypeptide (chronic granulomatous disease) | Nox2 | 3.5 | The Nox prototype Nox2 is the phagocytic Nox (also also known as gp91 phox |
| 2578 | CYBB | cytochrome b-245, beta polypeptide (chronic granulomatous disease) | Nox2 | 3.5 | Nox2 contains an NADPH-binding site a FAD-binding site and 4 heme-binding |
| 2578 | CYBB | cytochrome b-245, beta polypeptide (chronic granulomatous disease) | Nox2 | 3.5 | Nox2 is constitutively associated with the transmembrane Nox stabilizing protein p22 |
| 2577 | CYBA | cytochrome b-245, alpha polypeptide | p22 | 0.8 | Nox2 is constitutively associated with the transmembrane Nox stabilizing protein p22 phox and recruitment of the activating cytosolic components p47 phox |
| 7660 | NCF1 | neutrophil cytosolic factor 1, (chronic granulomatous disease, autosomal 1) | p47 | 0.6 | protein p22 phox and recruitment of the activating cytosolic components p47 phox p67 phox and p40 phox are needed for function |
| 7661 | NCF2 | neutrophil cytosolic factor 2 (65kDa, chronic granulomatous disease, autosomal 2) | p67 | 0.3 | phox and recruitment of the activating cytosolic components p47 phox p67 phox and p40 phox are needed for function (Figure Figure |
| 7662 | NCF4 | neutrophil cytosolic factor 4, 40kDa | p40 | 0.6 | of the activating cytosolic components p47 phox p67 phox and p40 phox are needed for function (Figure Figure 1 |
| 7660 | NCF1 | neutrophil cytosolic factor 1, (chronic granulomatous disease, autosomal 1) | p47 | 0.6 | Upon cell activation p47 phox is phosphorylated thereby initiating translocation of the p47 phox |
| 7660 | NCF1 | neutrophil cytosolic factor 1, (chronic granulomatous disease, autosomal 1) | p47 | 0.6 | activation p47 phox is phosphorylated thereby initiating translocation of the p47 phox /p67 p67 phox /p40 p40 phox complex to the |
| 7661 | NCF2 | neutrophil cytosolic factor 2 (65kDa, chronic granulomatous disease, autosomal 2) | p67 | 0.3 | is phosphorylated thereby initiating translocation of the p47 phox /p67 p67 phox /p40 p40 phox complex to the membrane where phosphorylated |
| 7662 | NCF4 | neutrophil cytosolic factor 4, 40kDa | p40 | 0.6 | initiating translocation of the p47 phox /p67 p67 phox /p40 p40 phox complex to the membrane where phosphorylated p47 phox binds |
| 7660 | NCF1 | neutrophil cytosolic factor 1, (chronic granulomatous disease, autosomal 1) | p47 | 0.6 | phox /p40 p40 phox complex to the membrane where phosphorylated p47 phox binds to p22 phox |
| 2577 | CYBA | cytochrome b-245, alpha polypeptide | p22 | 0.8 | complex to the membrane where phosphorylated p47 phox binds to p22 phox |
| 670 | RHOD | ras homolog gene family, member D | Rho | 0.3 | Another level of regulation comes from members of the Rho family of small GTPases including the Rac family |
| 391 | AKT1 | v-akt murine thymoma viral oncogene homolog 1 | Rac | 0.0 | members of the Rho family of small GTPases including the Rac family |
| 391 | AKT1 | v-akt murine thymoma viral oncogene homolog 1 | Rac | 0.0 | Members of the Rac family are not strictly NADPH subunits as they regulate other |
| 7660 | NCF1 | neutrophil cytosolic factor 1, (chronic granulomatous disease, autosomal 1) | p47 | 0.6 | Rac acts to coordinate the translocation of the p47 phox /p67 p67 phox /p40 p40 phox complex and is |
| 7661 | NCF2 | neutrophil cytosolic factor 2 (65kDa, chronic granulomatous disease, autosomal 2) | p67 | 0.3 | acts to coordinate the translocation of the p47 phox /p67 p67 phox /p40 p40 phox complex and is active only when |
| 7662 | NCF4 | neutrophil cytosolic factor 4, 40kDa | p40 | 0.6 | the translocation of the p47 phox /p67 p67 phox /p40 p40 phox complex and is active only when bound to GTP |
| 391 | AKT1 | v-akt murine thymoma viral oncogene homolog 1 | Rac | 0.0 | Rac acts to coordinate the translocation of the p47 phox /p67 |
| 391 | AKT1 | v-akt murine thymoma viral oncogene homolog 1 | Rac | 0.0 | Inactivation of Rac is mediated via GTPase-activating proteins which stimulate the intrinsic ability |
| 391 | AKT1 | v-akt murine thymoma viral oncogene homolog 1 | Rac | 0.0 | mediated via GTPase-activating proteins which stimulate the intrinsic ability of Rac to hydrolyze GTP to GDP |
| 7889 | NOX1 | NADPH oxidase 1 | Nox1 | 1.2 | all Nox family members require the same interacting partners but Nox1 and Nox2 are both p47 phox and Rac dependent ( |
| 2578 | CYBB | cytochrome b-245, beta polypeptide (chronic granulomatous disease) | NOX2 | 3.5 | all Nox family members require the same interacting partners but Nox1 and Nox2 are both p47 phox and Rac dependent ( |
| 2578 | CYBB | cytochrome b-245, beta polypeptide (chronic granulomatous disease) | Nox2 | 3.5 | family members require the same interacting partners but Nox1 and Nox2 are both p47 phox and Rac dependent ( 15 |
| 7660 | NCF1 | neutrophil cytosolic factor 1, (chronic granulomatous disease, autosomal 1) | p47 | 0.6 | the same interacting partners but Nox1 and Nox2 are both p47 phox and Rac dependent ( 15 |
| 391 | AKT1 | v-akt murine thymoma viral oncogene homolog 1 | Rac | 0.0 | partners but Nox1 and Nox2 are both p47 phox and Rac dependent ( 15 |
| 2578 | CYBB | cytochrome b-245, beta polypeptide (chronic granulomatous disease) | Nox2 | 3.5 | This scenario is consistent with protection observed by Nox2 deletion in other models of neurodegeneration in which inflammation has |
| 2578 | CYBB | cytochrome b-245, beta polypeptide (chronic granulomatous disease) | Nox2 | 3.5 | In addition dopaminergic neurons cocultured with microglial cells lacking the Nox2 gene are more resistant to rotenone-induced neuronal death ( 18 |
| 620 | APP | amyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease) | amyloid | 1.0 | to rotenone-induced neuronal death ( 18 and Alzheimer disease_amp_#x02013 linked amyloid peptides (derived derived from neurons activate microglial cells to produce |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.5 | However in the case of ALS associated with SOD1 mutations the new data reported by Harraz Engelhardt and colleagues |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.5 | ( 20 provide a direct link between the disease-causing mutant SOD1 and Nox-mediated ROS production by microglial cells through SOD1 binding |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.5 | mutant SOD1 and Nox-mediated ROS production by microglial cells through SOD1 binding to the Nox activator Rac1 thereby influencing the non_amp_#x02013 |
| 9801 | RAC1 | ras-related C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1) | Rac1 | 1.0 | by microglial cells through SOD1 binding to the Nox activator Rac1 thereby influencing the non_amp_#x02013 cell autonomous killing of motor neurons |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.5 | Mutant SOD1 stimulates Rac1-GTP activation of Nox and production of ROS |
| 9801 | RAC1 | ras-related C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1) | Rac1 | 1.0 | Using an approach involving immunoprecipitation of Rac1 from different mouse tissues Harraz and colleagues proposed that SOD1 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.5 | Rac1 from different mouse tissues Harraz and colleagues proposed that SOD1 interacts directly with Rac1 but not with the other Nox2 |
| 9801 | RAC1 | ras-related C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1) | Rac1 | 1.0 | tissues Harraz and colleagues proposed that SOD1 interacts directly with Rac1 but not with the other Nox2 cytosolic regulators ( 20 |
| 2578 | CYBB | cytochrome b-245, beta polypeptide (chronic granulomatous disease) | Nox2 | 3.5 | SOD1 interacts directly with Rac1 but not with the other Nox2 cytosolic regulators ( 20 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1-interacting | 2.2 | It is puzzling why multiple earlier screens for SOD1-interacting proteins including yeast 2-hybrid approaches did not identify Rac1 |
| 9801 | RAC1 | ras-related C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1) | Rac1 | 1.0 | for SOD1-interacting proteins including yeast 2-hybrid approaches did not identify Rac1 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.5 | _amp_#x02013 that is converted to H 2 O 2 by SOD1 it was further tested whether the enzymatic activity of SOD1 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.5 | SOD1 it was further tested whether the enzymatic activity of SOD1 was important for this interaction of SOD1 with Rac1 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.5 | enzymatic activity of SOD1 was important for this interaction of SOD1 with Rac1 |
| 9801 | RAC1 | ras-related C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1) | Rac1 | 1.0 | of SOD1 was important for this interaction of SOD1 with Rac1 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.5 | Only the metalated (native) native form of SOD1 bound to Rac1 while the demetalated (enzymatically enzymatically inactive SOD1 |
| 9801 | RAC1 | ras-related C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1) | Rac1 | 1.0 | Only the metalated (native) native form of SOD1 bound to Rac1 while the demetalated (enzymatically enzymatically inactive SOD1 did not |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.5 | SOD1 bound to Rac1 while the demetalated (enzymatically enzymatically inactive SOD1 did not |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.5 | In addition the binding of SOD1 to Rac1 was redox sensitive and could be cycled between |
| 9801 | RAC1 | ras-related C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1) | Rac1 | 1.0 | In addition the binding of SOD1 to Rac1 was redox sensitive and could be cycled between bound and |
| 9801 | RAC1 | ras-related C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1) | Rac1 | 1.0 | bound and unbound states depending on the redox state of Rac1 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.5 | Under reducing conditions SOD1 efficiently bound Rac1-GTP the form of Rac1 that is recruited |
| 9801 | RAC1 | ras-related C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1) | Rac1 | 1.0 | Under reducing conditions SOD1 efficiently bound Rac1-GTP the form of Rac1 that is recruited to Nox2 upon activation |
| 2578 | CYBB | cytochrome b-245, beta polypeptide (chronic granulomatous disease) | Nox2 | 3.5 | bound Rac1-GTP the form of Rac1 that is recruited to Nox2 upon activation |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.5 | The binding of SOD1 to Rac1-GTP inhibited the intrinsic and/or and or GAP-facilitated GTPase |
| 9801 | RAC1 | ras-related C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1) | Rac1 | 1.0 | inhibited the intrinsic and/or and or GAP-facilitated GTPase activity of Rac1 (Figure Figure 1 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.5 | It is now widely accepted that ALS-linked mutations in SOD1 provoke disease due to the acquisition of one or more |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.5 | the acquisition of one or more toxic properties of mutant SOD1 ( 2 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.5 | in tissues from mice expressing the catalytically active ALS-linked mutant SOD1 G93A but not in tissues from mice expressing comparably high |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.5 | not in tissues from mice expressing comparably high levels of SOD1 WT (Figure Figure 1 and ref 20 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.5 | also seen in glial and neuronal cell lines expressing mutant SOD1 G93A and SOD1 L8Q but not SOD1 WT and was |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.5 | glial and neuronal cell lines expressing mutant SOD1 G93A and SOD1 L8Q but not SOD1 WT and was accompanied by increased |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.5 | lines expressing mutant SOD1 G93A and SOD1 L8Q but not SOD1 WT and was accompanied by increased cell death |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.5 | In addition liver tissues from SOD1 G93A mice _amp_#x02014 in which no altered pathology is normally |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.5 | _amp_#x02022 _amp_#x02013 in agreement with a direct effect of mutant SOD1 on Nox activation rather than a consequence of increased inflammation |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.5 | direct effect of increased ROS as a result of mutant SOD1 within microglial cells obviously could influence the survival of motor |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.5 | demonstrations of slowed disease progression after reducing or eliminating mutant SOD1 synthesis within the myeloid lineage ( 11 12 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.5 | between increased production of O 2 _amp_#x02022 _amp_#x02013 by mutant SOD1 and elevated Rac1-GTP levels was seen not just for SOD1 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.5 | SOD1 and elevated Rac1-GTP levels was seen not just for SOD1 G93A but also for 2 additional ALS-linked SOD1 mutants SOD1 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.5 | just for SOD1 G93A but also for 2 additional ALS-linked SOD1 mutants SOD1 L8Q and SOD1 G10V ( 20 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.5 | SOD1 G93A but also for 2 additional ALS-linked SOD1 mutants SOD1 L8Q and SOD1 G10V ( 20 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.5 | also for 2 additional ALS-linked SOD1 mutants SOD1 L8Q and SOD1 G10V ( 20 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.5 | property of the more than 115 different mutations in the SOD1 gene known to cause ALS |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.5 | is independent of dismutase activity with multiple mutants (including including SOD1 G85R SOD1 H46R and SOD1 G127X shown to be causative |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.5 | of dismutase activity with multiple mutants (including including SOD1 G85R SOD1 H46R and SOD1 G127X shown to be causative for disease |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.5 | with multiple mutants (including including SOD1 G85R SOD1 H46R and SOD1 G127X shown to be causative for disease in humans and |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.5 | Similarly the failure of demetalated SOD1 WT to bind and activate Rac1-GTP would predict that removal |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.5 | Rac1-GTP would predict that removal of the copper chaperone for SOD1 (CCS) CCS would substantially slow disease but this was not |
| 1613 | CCS | copper chaperone for superoxide dismutase | CCS | 1.2 | predict that removal of the copper chaperone for SOD1 (CCS) CCS would substantially slow disease but this was not the case |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.5 | Thus only if SOD1 mutants increase Nox2 activity independently of their metalated state could |
| 2578 | CYBB | cytochrome b-245, beta polypeptide (chronic granulomatous disease) | Nox2 | 3.5 | Thus only if SOD1 mutants increase Nox2 activity independently of their metalated state could mutant SOD1_amp_#x02013 enhanced |
| 9801 | RAC1 | ras-related C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1) | Rac1 | 1.0 | activity independently of their metalated state could mutant SOD1_amp_#x02013 enhanced Rac1 activation and Nox-dependent O 2 _amp_#x02022 _amp_#x02013 production be a |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.5 | be a feature common to the broader set of ALS-linked SOD1 mutants |
| 2578 | CYBB | cytochrome b-245, beta polypeptide (chronic granulomatous disease) | Nox2 | 3.5 | Decreasing ROS production by deleting Nox2 has already proven efficacious in ALS mice ( 13 14 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.5 | The addition of apocynin to the drinking water of SOD1 G93A ALS mice beginning at 2 weeks of age increased |
| 2578 | CYBB | cytochrome b-245, beta polypeptide (chronic granulomatous disease) | Nox2 | 3.5 | and in fact greater than _amp_#x02014 the deletion of the Nox2 gene in SOD1 G93A mice previously reported by the same |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.5 | greater than _amp_#x02014 the deletion of the Nox2 gene in SOD1 G93A mice previously reported by the same group ( 14 |
| 7660 | NCF1 | neutrophil cytosolic factor 1, (chronic granulomatous disease, autosomal 1) | p47 | 0.6 | Apocynin is believed to block the translocation of p47 phox /p67 p67 phox to Nox ( 23 and would |
| 7661 | NCF2 | neutrophil cytosolic factor 2 (65kDa, chronic granulomatous disease, autosomal 2) | p67 | 0.3 | is believed to block the translocation of p47 phox /p67 p67 phox to Nox ( 23 and would therefore inhibit only |
| 7889 | NOX1 | NADPH oxidase 1 | Nox1 | 1.2 | only the Nox proteins requiring these cytosolic activators which include Nox1 and Nox2 |
| 2578 | CYBB | cytochrome b-245, beta polypeptide (chronic granulomatous disease) | NOX2 | 3.5 | only the Nox proteins requiring these cytosolic activators which include Nox1 and Nox2 |
| 2578 | CYBB | cytochrome b-245, beta polypeptide (chronic granulomatous disease) | Nox2 | 3.5 | Nox proteins requiring these cytosolic activators which include Nox1 and Nox2 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.5 | a neuronal cell line when cells were transfected with mutant SOD1 ( 20 providing support that apocynin effectiveness may be acting |
| 2578 | CYBB | cytochrome b-245, beta polypeptide (chronic granulomatous disease) | Nox2 | 3.5 | Although expression of Nox2 by neurons astrocytes and endothelial cells has been reported ( |
| 2578 | CYBB | cytochrome b-245, beta polypeptide (chronic granulomatous disease) | Nox2 | 3.5 | and endothelial cells has been reported ( 15 staining for Nox2 in ALS mice only revealed accumulation in microglial cells ( |
| 7889 | NOX1 | NADPH oxidase 1 | Nox1 | 1.2 | However other Nox proteins are expressed in the CNS including Nox1 in neurons and endothelial cells Nox4 in astrocytes neurons and |
| 7891 | NOX4 | NADPH oxidase 4 | Nox4 | 0.9 | in the CNS including Nox1 in neurons and endothelial cells Nox4 in astrocytes neurons and endothelial cells and Nox5 in endothelial |
| 14874 | NOX5 | NADPH oxidase, EF-hand calcium binding domain 5 | Nox5 | 0.9 | endothelial cells Nox4 in astrocytes neurons and endothelial cells and Nox5 in endothelial cells moreover high doses of apocynin have been |
| 7891 | NOX4 | NADPH oxidase 4 | Nox4 | 0.9 | moreover high doses of apocynin have been reported to inhibit Nox4 and Nox5 ( 15 |
| 14874 | NOX5 | NADPH oxidase, EF-hand calcium binding domain 5 | NOX5 | 0.9 | moreover high doses of apocynin have been reported to inhibit Nox4 and Nox5 ( 15 |
| 14874 | NOX5 | NADPH oxidase, EF-hand calcium binding domain 5 | Nox5 | 0.9 | doses of apocynin have been reported to inhibit Nox4 and Nox5 ( 15 |
| 2578 | CYBB | cytochrome b-245, beta polypeptide (chronic granulomatous disease) | Nox2 | 3.5 | Of relevance for patients Nox2 upregulation has been reported in spinal cords of sporadic ALS |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.5 | ( 13 but it is still unknown whether patients with SOD1 mutations generate similar or greater increases in Nox2 activity or |
| 2578 | CYBB | cytochrome b-245, beta polypeptide (chronic granulomatous disease) | Nox2 | 3.5 | patients with SOD1 mutations generate similar or greater increases in Nox2 activity or expression |
| 2578 | CYBB | cytochrome b-245, beta polypeptide (chronic granulomatous disease) | Nox2 | 3.5 | Two reported studies of ALS mice with a Nox2 deletion reached divergent conclusions one group described downregulation of microglial |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.5 | in the progression of disease and whether apocynin affects mutant SOD1 expression |
| 2578 | CYBB | cytochrome b-245, beta polypeptide (chronic granulomatous disease) | Nox2 | 3.5 | Mutations altering the activity of Nox2 (or or other subunits of Nox are known to cause |
| 2578 | CYBB | cytochrome b-245, beta polypeptide (chronic granulomatous disease) | CGD | 2.5 | of Nox are known to cause chronic granulomatous disease (CGD) CGD ( 15 which is characterized by severe and chronic infections |
| 2578 | CYBB | cytochrome b-245, beta polypeptide (chronic granulomatous disease) | CGD | 2.5 | CGD patients are usually chronically administered antibiotics and IFN-_amp_#x003b3 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.5 | disease and might therefore be a direct consequence of mutant SOD1 expression in the infected tissues deprived of Nox activity rather |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.5 | With this new finding that interaction of metalated SOD1 with Rac1 serves to activate Nox2 and that mutant forms |
| 9801 | RAC1 | ras-related C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1) | Rac1 | 1.0 | With this new finding that interaction of metalated SOD1 with Rac1 serves to activate Nox2 and that mutant forms of SOD1 |
| 2578 | CYBB | cytochrome b-245, beta polypeptide (chronic granulomatous disease) | Nox2 | 3.5 | that interaction of metalated SOD1 with Rac1 serves to activate Nox2 and that mutant forms of SOD1 amplify production of ROS |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.5 | Rac1 serves to activate Nox2 and that mutant forms of SOD1 amplify production of ROS by locking Nox2 in its activated |
| 2578 | CYBB | cytochrome b-245, beta polypeptide (chronic granulomatous disease) | Nox2 | 3.5 | mutant forms of SOD1 amplify production of ROS by locking Nox2 in its activated state Harraz and colleagues have advanced a |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.5 | new hypothesis for the gain of toxic function of mutant SOD1 ( 20 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.5 | Indeed normal SOD1 function typically defined only by its dismutase activity is now |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.5 | of these additional properties could be induced by mutations in SOD1 as one of the toxic contributors in ALS |
| 14874 | NOX5 | NADPH oxidase, EF-hand calcium binding domain 5 | nadph oxidase | 1.0 | in this issue of the jci harraz and colleagues demonstrate that sod1 mutants expressed in human cell lines directly stimulate nadph oxidase nox by binding to rac1 resulting in overproduction of damaging ros see the related article beginning on page 659 . |
| 14874 | NOX5 | NADPH oxidase, EF-hand calcium binding domain 5 | nadph oxidase | 1.0 | footnotes nonstandard abbreviations used: als amyotrophic lateral sclerosis; nox nadph oxidase; o 2 _amp_#x02022;_amp_#x02013; superoxide; sod1 superoxide dismutase_amp_#x02013;1. |
| 2578 | CYBB | cytochrome b-245, beta polypeptide (chronic granulomatous disease) | gp91 phox | 1.0 | the nox prototype nox2 is the phagocytic nox also known as gp91 phox that generates o 2 _amp_#x02022;_amp_#x02013; not as a byproduct but as a primary function of the enzyme 15 . |
| 2577 | CYBA | cytochrome b-245, alpha polypeptide | p22 phox | 1.0 | nox2 is constitutively associated with the transmembrane nox stabilizing protein p22 phox and recruitment of the activating cytosolic components p47 phox p67 phox and p40 phox are needed for function figure 1 . |
| 7661 | NCF2 | neutrophil cytosolic factor 2 (65kDa, chronic granulomatous disease, autosomal 2) | p67 phox | 1.0 | nox2 is constitutively associated with the transmembrane nox stabilizing protein p22 phox and recruitment of the activating cytosolic components p47 phox p67 phox and p40 phox are needed for function figure 1 . |
| 2577 | CYBA | cytochrome b-245, alpha polypeptide | p22 phox | 1.0 | upon cell activation p47 phox is phosphorylated thereby initiating translocation of the p47 phox /p67 phox /p40 phox complex to the membrane where phosphorylated p47 phox binds to p22 phox . |
| 7661 | NCF2 | neutrophil cytosolic factor 2 (65kDa, chronic granulomatous disease, autosomal 2) | p67 phox | 1.0 | upon cell activation p47 phox is phosphorylated thereby initiating translocation of the p47 phox /p67 phox /p40 phox complex to the membrane where phosphorylated p47 phox binds to p22 phox . |
| 7661 | NCF2 | neutrophil cytosolic factor 2 (65kDa, chronic granulomatous disease, autosomal 2) | p67 phox | 1.0 | rac acts to coordinate the translocation of the p47 phox /p67 phox /p40 phox complex and is active only when bound to gtp not when bound to gdp. |
| 7661 | NCF2 | neutrophil cytosolic factor 2 (65kDa, chronic granulomatous disease, autosomal 2) | p67 phox | 1.0 | apocynin is believed to block the translocation of p47 phox /p67 phox to nox 23 and would therefore inhibit only the nox proteins requiring these cytosolic activators which include nox1 and nox2. |
| 7661 | NCF2 | neutrophil cytosolic factor 2 (65kDa, chronic granulomatous disease, autosomal 2) | chronic granulomatous disease | 1.0 | mutations altering the activity of nox2 or other subunits of nox are known to cause chronic granulomatous disease cgd 15 which is characterized by severe and chronic infections that are hard to treat due to the incapacity of immune cells to produce o 2 _amp_#x02022;_amp_#x02013; and therefore to fight pathogens. |