)| PMID |
11513882 ( ) |
|---|---|
| Title | Superoxide dismutase mutations of familial amyotrophic lateral sclerosis and the oxidative inactivation of calcineurin. |
| Abstract | Approximately 10% of all familial cases of amyotrophic lateral sclerosis (fALS) are linked to mutations in the SOD1 gene, which encodes the copper/zinc superoxide dismutase (CuZnSOD). Recently, wild-type CuZnSOD was shown to protect calcineurin, a calcium/calmodulin-regulated phosphoprotein phosphatase, from inactivation by reactive oxygen species. We asked whether the protective effect of CuZnSOD on calcineurin is affected by mutations associated with fALS. For this, we monitored calcineurin activity in the presence of mutant and wild-type SOD. We found that the degree of protection against inactivation of calcineurin by different SOD mutants correlates with the severity of the phenotype associated with the different mutations, suggesting a potential role for calcineurin-SOD1 interaction in the etiology of fALS. |
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Targets by SciMiner Summary
| HUGO ID | Symbol | Target Name | #Occur | ActualStr |
|---|---|---|---|---|
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | 72 | hSOD | SOD1 | SOD1s | SODs | SOD-generated | superoxide dismutase | |
| 9577 | PSPH | phosphoserine phosphatase | 2 | phosphoserine phosphatase | |
| 4571 | GRIA1 | glutamate receptor, ionotropic, AMPA 1 | 1 | glutamate receptor | |
| 1442 | CALM1 | calmodulin 1 (phosphorylase kinase, delta) | 1 | calmodulin 1 | |
Targets by SciMiner Full list
| HUGO ID | Symbol | Name | ActualStr | Score | FlankingText |
|---|---|---|---|---|---|
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 6.0 | lateral sclerosis (fALS) fALS are linked to mutations in the SOD1 gene which encodes the copper/zinc copper zinc superoxide dismutase (CuZnSOD) |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD | 4.3 | monitored calcineurin activity in the presence of mutant and wild-type SOD |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD | 4.3 | the degree of protection against inactivation of calcineurin by different SOD mutants correlates with the severity of the phenotype associated with |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 6.0 | with the different mutations suggesting a potential role for calcineurin_amp_#x2013 SOD1 interaction in the etiology of fALS |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 6.0 | Mutations in the SOD1 gene which encodes the enzyme copper/zinc copper zinc superoxide dismutase |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 6.0 | Today more than 70 different mutations of the SOD1 gene are known ranging from mutations that are associated with |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 6.0 | Recently it was shown that SOD1 protects calcineurin a serine/threonine-specific serine threonine-specific calcium/calmodulin-dependent calcium calmodulin-dependent phosphoprotein |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 6.0 | the last years the primary molecular targets of the mutated SOD1 in fALS are still unknown |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SODs | 2.2 | In this study we report that the mutant SODs were significantly less protective against calcineurin inactivation and that the |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SODs | 2.2 | Wt and mutant SODs were purified and demetalated by Ni-NTA-affinity chromatography using imidazole (500 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD | 4.3 | SOD assay and activity staining |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD | 4.3 | For atomic emission spectrometry (AES), AES SOD proteins were washed five times in refolding buffer (Centrex Centrex |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD | 4.3 | okadaic acid (5 5 _amp_#x3bc m 200 _amp_#x3bc g of SOD proteins and water ad 40 _amp_#x3bc l |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 6.0 | test the hypothesis that calcineurin is a target of mutated SOD1 we used recombinant wt enzyme and three variants associated with |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD | 4.3 | native electropherograms with NBT showed a corresponding pattern with wt SOD showing the highest activity followed by the D90A mutant whereas |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SODs | 2.2 | conveyed the most protection of calcineurin activity of the mutant SODs studied |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD | 4.3 | loss of over 60% of the protection confered by wt SOD |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD | 4.3 | This effect was not due to reduced SOD activity of the mutant SODs compared to wt when the |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SODs | 2.2 | was not due to reduced SOD activity of the mutant SODs compared to wt when the amounts of wt or mutant |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD | 4.3 | compared to wt when the amounts of wt or mutant SOD were quadrupled (800 800 ng the loss of protection of |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD | 4.3 | calcineurin activity was magnified rather than reduced for the fALS SOD mutants ( Fig 2b dark bars however the differences in |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD | 4.3 | While wt SOD maintained its protective effect on calcineurin activity and co-incubation of |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SODs | 2.2 | effect on calcineurin activity and co-incubation of calcineurin with the SODs associated with benign (D9OA) D9OA and classic (G93A) G93A fALS |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD | 4.3 | only showed a slight reduction compared to 200 ng of SOD the SOD associated with the most severe form of fALS |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD | 4.3 | a slight reduction compared to 200 ng of SOD the SOD associated with the most severe form of fALS (A4V) A4V |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | hSOD | 2.2 | activity meaning that over 80% of the protection of wt hSOD were lost due to this mutation |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD | 4.3 | To address the observation that increased amounts of mutant SOD compounded the loss of calcineurin activity we tested a mixture |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SODs | 2.2 | Our results thus demonstrate that mutant SODs can reduce the protection conferred by wt SOD |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD | 4.3 | that mutant SODs can reduce the protection conferred by wt SOD |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 6.0 | This observation supports the hypothesis that the SOD1 mutations found in fALS result in a negative gain of |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD | 4.3 | in a reduction of the protection of calcineurin by wt SOD |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD | 4.3 | How the different mutations in the ubiquitously expressed enzyme SOD cause the highly specific neuropathological phenotype associated with fALS remains |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD | 4.3 | CuZnSOD 5 which itself accounts for 2% of brain protein SOD and calcineurin are both among the most abundant proteins in |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SODs | 2.2 | In this study we report that mutated SODs loose their capacity to protect calcineurin from oxidative inactivation as |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD | 4.3 | The SOD mutant showing the least protective effect (A4V) A4V is associated |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 6.0 | reduced calcineurin activity in human neuroblastoma cells transfected with mutated SOD1 and in the forebrains of fALS-transgenic mice 9 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD | 4.3 | Moreover when the amount of SOD protein was quadrupled in the assay the wt maintained its |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD | 4.3 | the wt CuZnSOD protein and not simply the presence of SOD activity is needed for the protection of calcineurin from oxidative |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD-generated | 2.2 | that the increased inactivation of calcineurin is mediated by mutated SOD-generated oxidative species different from superoxide a hypothesis that has already |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD | 4.3 | be in accordance with the notion that overexpression of wt SOD together with fALS-associated SOD is not protective 21 an observation |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD | 4.3 | the notion that overexpression of wt SOD together with fALS-associated SOD is not protective 21 an observation that is strengthened by |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SODs | 2.2 | by the fact that a mixture of wt and mutant SODs only confers an intermediate rate of protection |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD | 4.3 | The partial protective effect of wt SOD when mixed with mutant SOD may be explained by the |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD | 4.3 | partial protective effect of wt SOD when mixed with mutant SOD may be explained by the necessity of SOD to bind |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD | 4.3 | with mutant SOD may be explained by the necessity of SOD to bind to calcineurin to exert its protective effect |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SODs | 2.2 | Wt and mutant SODs therefore would compete for binding to calcineurin so that part |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD | 4.3 | of the calcineurin molecules still could be protected by wt SOD |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 6.0 | It has to be noted however that the recombinant reconstituted SOD1 proteins used in this study show an abnormal zinc content |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 6.0 | A reduced affinity of SOD1 mutants for zinc is an observation that has already been |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 6.0 | However our wt SOD1 gives exactly the same rate of protection as SOD1 purified |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 6.0 | wt SOD1 gives exactly the same rate of protection as SOD1 purified from erythrocytes and the D90A mutation which shows a |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SODs | 2.2 | of our results a reduction of calcineurin activity by mutant SODs would therefore lead to prolonged NMDA receptor-channel openings and therefore |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 6.0 | This would explain why glutamate potentiates the toxicity of mutant SOD1 in motor neurons 22 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SODs | 2.2 | systems and a higher Ca content in cells expressing mutant SODs or in mutant SOD1 transgenic mice has been observed 23 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 6.0 | Ca content in cells expressing mutant SODs or in mutant SOD1 transgenic mice has been observed 23 24 and 25 a |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 6.0 | Characterization of the SOD1 proteins |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 6.0 | The recombinant SOD1 proteins are characterized by a reduced activity and a reduced |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 6.0 | Lower panel Activity staining of recombinant SOD1 proteins |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD | 4.3 | activity can be preserved by addition of erythrocyte (ery) ery SOD or recombinant human (hr) hr SOD |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD | 4.3 | of erythrocyte (ery) ery SOD or recombinant human (hr) hr SOD |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SODs | 2.2 | Recombinant mutant SODs associated with fALS are less protective |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SODs | 2.2 | Addition of quadruple amounts of wt or mutant SODs (black black bars reduces the protective ability of the mutants |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD | 4.3 | n =6 * P _amp_#x3c 0.05 significantly different from wt SOD by Student_amp_#x2019 s t -test ** P _amp_#x3c 0.01 significantly |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD | 4.3 | t -test ** P _amp_#x3c 0.01 significantly different from wt SOD by Student_amp_#x2019 s t -test |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SODs | 2.2 | A mixture of wt and mutant SODs confers intermediate protection |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD | 4.3 | Addition of wt SOD (400 400 ng to mutant SOD1s (400 400 ng results |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1s | 2.2 | Addition of wt SOD (400 400 ng to mutant SOD1s (400 400 ng results in intermediate protective ability against oxidative |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD | 4.3 | n =4 ** P _amp_#x3c 0.01 significantly different from mutant SOD alone by Student_amp_#x2019 s t -test |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | superoxide dismutase | 1.0 | approximately 10% of all familial cases of amyotrophic lateral sclerosis fals are linked to mutations in the sod1 gene which encodes the copper/zinc superoxide dismutase cuznsod . |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | superoxide dismutase | 1.0 | mutations in the sod1 gene which encodes the enzyme copper/zinc superoxide dismutase are associated with familial amyotrophic lateral sclerosis fals a fatal neurodegenerative disorder affecting spinal cord and brain motor neurons [ 1 ]. |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | superoxide dismutase | 1.0 | in order to address our hypothesis that calcineurin is one of the targets we investigated the ability of four different copper/zinc superoxide dismutase cuznsod proteins three mutant forms and the wild type wt enzyme to protect calcineurin from oxidative inactivation in vitro. |
| 9577 | PSPH | phosphoserine phosphatase | phosphoserine phosphatase | 1.0 | phosphoserine phosphatase assay was performed as described previously [ 5 and 15 ]. |
| 1442 | CALM1 | calmodulin 1 (phosphorylase kinase, delta) | calmodulin 1 | 1.0 | in brief 40 _amp_#x3bc;l recombinant or partially purified calcineurin was mixed with test buffer 40 mm tris_amp_#x2013;hcl ph 8 0.1 m kcl 0.4 mg/ml bsa 0.67 mm dtt 0.67 _amp_#x3bc;m calmodulin 1 _amp_#x3bc;m fkbp and 0.5 _amp_#x3bc;m okadaic acid for inhibition of phophotase a1 and a2 . |
| 9577 | PSPH | phosphoserine phosphatase | phosphoserine phosphatase | 1.0 | incubation of calcineurin for 20 min at 30_amp_#xb0;c under aerobic conditions in the presence of calcium led to a rapid loss of phosphoserine phosphatase activity to 5_amp_#x2013;8% of baseline activity fig 2a . |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | superoxide dismutase | 1.0 | therefore calcineurin would be an ideal candidate for a proposed influence of superoxide dismutase mutations on signal transduction pathways leading to a mutant steady state finally resulting in neurodegeneration. |
| 4571 | GRIA1 | glutamate receptor, ionotropic, AMPA 1 | glutamate receptor | 1.0 | since the calcineurin inactivation is dependent on the presence of calcium motoneurons which are subject to glutamate receptor mediated ca 2+ influxes may be especially at risk for calcineurin inactivation. |