)| PMID |
12909279 ( ) |
|---|---|
| Title | Neurodegeneration in amyotrophic lateral sclerosis: the role of oxidative stress and altered homeostasis of metals. |
| Abstract | Amyotrophic lateral sclerosis is one of the most common neurodegenerative disorders, with an incidence of about 1/100,000. One of the typical features of this progressive, lethal disease, occurring both sporadically and as a familial disorder, is degeneration of cortical and spinal motor neurones. Present evidence indicates that loss of neurones in patients results from a complex interplay among oxidative injury, excitotoxic stimulation, dysfunction of critical proteins and genetic factors. This review focuses on existing evidence that oxidative stress is a major culprit in the pathogenesis of amyotrophic lateral sclerosis. An increase in reactive oxygen species and in products of oxidation has been observed both in post-mortem samples and in experimental models for ALS. This increase may be consequent to altered metabolism of copper and iron ions, that share the property to undergo redox cycling and generate reactive oxygen species. Metal-mediated oxidative stress would lead to several intracellular alterations and contribute to the induction of cell death pathways. Ricerca Scientifica, 00133 Rome, Italy. carri@Bio.uniroma2.it |
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)) | 48 | SOD-like | SOD1 | SOD1-linked | SOD1s | superoxide dismutase | sod1 | SOD-defective | |
| 9605 | PTGS2 | prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase) | 8 | COX2 | cox2 | |
| 1613 | CCS | copper chaperone for superoxide dismutase | 3 | CCS | |
| 1516 | CAT | catalase | 2 | catalase | |
| 6115 | IREB2 | iron-responsive element binding protein 2 | 2 | IRP-2 | |
| 9353 | PRDX2 | peroxiredoxin 2 | 2 | PrP | |
| 2295 | CP | ceruloplasmin (ferroxidase) | 2 | ferroxidase | ceruloplasmin | |
| 7872 | NOS1 | nitric oxide synthase 1 (neuronal) | 2 | NOS | |
| 11763 | TFRC | transferrin receptor (p90, CD71) | 1 | transferrin receptor | |
| 118 | ACO2 | aconitase 2, mitochondrial | 1 | aconitase | |
| 798 | ATOX1 | ATX1 antioxidant protein 1 homolog (yeast) | 1 | Atx1 | |
| 10417 | RPS27A | ribosomal protein S27a | 1 | ubiquitin | |
| 7873 | NOS2A | nitric oxide synthase 2A (inducible, hepatocytes) | 1 | nitric oxide synthase | |
| 2264 | COX17 | COX17 cytochrome c oxidase assembly homolog (S. cerevisiae) | 1 | COX17 | |
| 12780 | WNT2 | wingless-type MMTV integration site family member 2 | 1 | IRP-regulated | |
| 31395 | COX8B | cytochrome c oxidase, subunit 8B pseudogene | 1 | cytochrome c oxidase | |
| 11740 | TF | transferrin | 1 | transferrin | |
Targets by SciMiner Full list
| HUGO ID | Symbol | Name | ActualStr | Score | FlankingText |
|---|---|---|---|---|---|
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.7 | coding for the antioxidant enzyme Cu Zn superoxide dismutase (SOD1) SOD1 have been reported in fALS patients 21 and 80 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.7 | SOD1 is a very well-characterised homodimeric enzyme present in virtually every |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.7 | SOD1 binds zinc and copper ions with the Cu atom playing |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.7 | Linkage studies have revealed that mutations in SOD1 are responsible for 10_amp_#x2013 15% of fALS cases 40 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.7 | To date there are about 100 different SOD1 point mutations ( www.als.org reported in fALS families with various |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.7 | and result in alteration of amino acids scattered throughout the SOD1 structure while some mutations affect the active site others are |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1s | 1.9 | For this reason the mechanisms through which expression of mutant SOD1s result in motoneuron injury and death are still controversial |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.7 | believed that the gain of a novel toxic function of SOD1 is responsible for the acquisition of the pathological phenotype |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.7 | SOD1 is an abundant component of many cell types accounting for |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.7 | _amp_#x201c conformational_amp_#x201d diseases formation of insoluble aggregates of misfolded mutant SOD1 contributes to cell death in fALS |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.7 | However it is still debated whether SOD1 aggregates represent a cause a correlate or a consequence of |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.7 | of sALS patients contain cytoplasmic aggregates that show immunoreactivity for SOD1 and ubiquitin similar inclusion bodies were also observed in SOD1-linked |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1-linked | 2.2 | SOD1 and ubiquitin similar inclusion bodies were also observed in SOD1-linked fALS patients 12 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.7 | More recent evidence questioned the relevance of SOD1 aggregates in the pathogenesis of fALS |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.7 | For instance it has been reported that formation of SOD1 aggregates is independent of induction of cell death 52 and |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.7 | SOD1 aggregates may be toxic through sequestration of other proteins required |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.7 | Also SOD1 aggregates may reduce proteasome activity needed for normal protein turnover |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1s | 1.9 | How mutant SOD1s cause oxidative stress and which molecules represent direct targets/propagators targets |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.7 | the active site could exacerbate the reported peroxidative activity of SOD1 as suggested by studies in vitro 100 and in vivo |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.7 | it has been suggested that aggregated but still active mutant SOD1 may mediate the formation of ROS |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.7 | uptake intracellular delivery from chaperones (e.g e.g copper chaperone for SOD1 (CCS), CCS COX17 and Atx1 to specific targets (such such |
| 1613 | CCS | copper chaperone for superoxide dismutase | CCS | 1.2 | delivery from chaperones (e.g e.g copper chaperone for SOD1 (CCS), CCS COX17 and Atx1 to specific targets (such such as SOD1 |
| 2264 | COX17 | COX17 cytochrome c oxidase assembly homolog (S. cerevisiae) | COX17 | 0.6 | from chaperones (e.g e.g copper chaperone for SOD1 (CCS), CCS COX17 and Atx1 to specific targets (such such as SOD1 and |
| 798 | ATOX1 | ATX1 antioxidant protein 1 homolog (yeast) | Atx1 | 1.3 | (e.g e.g copper chaperone for SOD1 (CCS), CCS COX17 and Atx1 to specific targets (such such as SOD1 and cytochrome c |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.7 | CCS COX17 and Atx1 to specific targets (such such as SOD1 and cytochrome c oxidase and/or and or storage in copper |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1-linked | 2.2 | This is not the case in SOD1-linked fALS in which no alteration of total copper content is |
| 1613 | CCS | copper chaperone for superoxide dismutase | CCS | 1.2 | content is observed not even in experimental conditions in which CCS is missing 90 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1-linked | 2.2 | This may be occurring in SOD1-linked fALS since it is known that many mutant SOD1s do |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1s | 1.9 | in SOD1-linked fALS since it is known that many mutant SOD1s do not bind metals properly in vitro and possibly in |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1s | 1.9 | ability to bind copper (and and zinc among different mutant SOD1s have been reported 42 this seems to be to a |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.7 | general characteristic of fALS-SOD1s reinforcing the previously suggested hypothesis that SOD1 plays a crucial role in copper buffering |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | sod1 | 2.7 | In man sod1 is present in a single copy per haploid genome and |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.7 | penetrance close to 1 with patients usually heterozygous for mutant SOD1 except for some families carrying the mutation D90A |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.7 | Therefore alteration of half of SOD1 molecules in patients may result in a relevant imbalance of |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.7 | of either copper buffering or copper chemistry especially considering that SOD1 is a very abundant protein representing up to 1% of |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.7 | models 16 and 32 inhibit the peroxidase activity of mutant SOD1 A4V and G93A in vitro 100 rescue elevation of ROS |
| 1613 | CCS | copper chaperone for superoxide dismutase | CCS | 1.2 | transgenic fALS-mice model alteration of Cu metabolism via removal of CCS does not induce decrease of serum Cp 90 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1-linked | 2.2 | Cp has been described 68 that could be altered in SOD1-linked fALS because of copper mishandling and cause iron mishandling |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD | 1.9 | yeast Saccharomyces cerevisiae 20 and 87 in which lack of SOD causes a substantial increase in the Fe demand of the |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD-defective | 1.9 | The increased Fe demand of the SOD-defective yeast cell may reflect its aim to continuously reconstitute the |
| 118 | ACO2 | aconitase 2, mitochondrial | aconitase | 1.3 | involved in mitochondrial metabolism such as Complex I 53 and aconitase 51 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.7 | an imbalance in ROS production_amp_#x2014 either caused directly by mutant SOD1 or indirectly by other mechanisms_amp_#x2014 could be responsible for damage |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1-linked | 2.2 | complexes has been reported in patients and in models for SOD1-linked fALS 19 49 60 61 and 101 and there is |
| 12780 | WNT2 | wingless-type MMTV integration site family member 2 | IRP-regulated | 0.5 | ii Fe_amp_#x2013 S-cluster status nor (iii) iii transcription of IRE_amp_#x2013 IRP-regulated genes have been studied in patients suffering from fALS or |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.7 | that the metal-mediated free radical generation derived either from mutant SOD1 or from mishandled metal ions might be related to the |
| 6115 | IREB2 | iron-responsive element binding protein 2 | IRP-2 | 1.2 | but also in the regulation of translation-regulatory factors such as IRP-2 a factor involved in intracellular iron metabolism which is broken |
| 6115 | IREB2 | iron-responsive element binding protein 2 | IRP-2 | 1.2 | In this view proteasomal inhibition may disrupt normal turnover of IRP-2 thus causing elevated Fe levels within the cell which_amp_#x2014 as |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1-linked | 2.2 | clinically indistinguishable therefore studies on the less frequent genetically inherited SOD1-linked form of the disease are thought to be potentially useful |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.7 | in order to understand cellular alterations induced by mutation of SOD1 17 and 48 up to date no study has shed |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.7 | patients and in the transgenic mice model (while while mutant SOD1 is expressed ubiquitously |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.7 | Therefore the neurotoxic effect of mutant SOD1 seems to be not a simple consequence of its expression |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.7 | findings indicating that neuroinflammatory processes mediate the pathogenic effect of SOD1 mutation (and, and more in general ALS pathogenesis |
| 7872 | NOS1 | nitric oxide synthase 1 (neuronal) | NOS | 1.2 | expression of several proteins such as nitric oxide synthase (NOS) NOS 93 and COX2 70 that might be involved in mechanisms |
| 9605 | PTGS2 | prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase) | COX2 | 1.3 | proteins such as nitric oxide synthase (NOS) NOS 93 and COX2 70 that might be involved in mechanisms of inflammation-mediated neurodegeneration |
| 9605 | PTGS2 | prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase) | COX2 | 1.3 | Indeed COX2 and NOS activity are dramatically increased in post-mortem spinal cord |
| 7872 | NOS1 | nitric oxide synthase 1 (neuronal) | NOS | 1.2 | Indeed COX2 and NOS activity are dramatically increased in post-mortem spinal cord samples from |
| 9605 | PTGS2 | prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase) | COX2 | 1.3 | Increased levels of COX2 and of the pro-inflammatory prostaglandin PGE2 were found in the |
| 9605 | PTGS2 | prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase) | COX2 | 1.3 | Treatment with a selective COX2 inhibitor markedly inhibits production of PGE2 in the spinal cord |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.7 | the only (partially) partially understood is the presence of mutant SOD1 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.7 | The general concept is that upon mutation SOD1 is partially misfolded and binds copper improperly |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD-like | 1.9 | In both cases evidence of SOD-like activity arising from copper bound to peptide A_amp_#x3b2 and to |
| 9353 | PRDX2 | peroxiredoxin 2 | PrP | 1.1 | from copper bound to peptide A_amp_#x3b2 and to the protein PrP respectively has been provided 11 and 47 |
| 9353 | PRDX2 | peroxiredoxin 2 | PrP | 1.1 | would not be surprising to learn that copper-bound A_amp_#x3b2 and PrP are also able to induce the formation of the noxious |
| 1516 | CAT | catalase | catalase | 1.0 | these include enzymatic activities superoxide dismutase catalase peroxidase and peroxiredoxin low molecular weight antioxidant species vitamin e ascorbate glutathione plus more complex forms of protection such as systems for metal transport and buffering and induc |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | superoxide dismutase | 1.0 | these include enzymatic activities superoxide dismutase catalase peroxidase and peroxiredoxin low molecular weight antioxidant species vitamin e ascorbate glutathione plus more complex forms of protection such as systems for metal transport and buffering |
| 1516 | CAT | catalase | catalase | 1.0 | the central nervous system cns is particularly sensitive to this kind of damage for a number of reasons including a low level of some antioxidant enzymes catalase and gsh peroxidase a high content of easily oxidised substrates e.g membrane polyunsaturated lipids and an inherently high flux of ros generated during neurochemical reactions such as dopamine oxidat |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | superoxide dismutase | 1.0 | to the concept that oxidative stress plays a major role in als as in other neurodegenerative diseases is provided by the observation that mutations in the gene coding for the antioxidant enzyme cu zn superoxide dismutase sod1 have been reported in fals patients [ 21 and 80 ]. |
| 10417 | RPS27A | ribosomal protein S27a | ubiquitin | 1.0 | in fact it is known that neurons and astrocytes of sals patients contain cytoplasmic aggregates that show immunoreactivity for sod1 and ubiquitin; similar inclusion bodies were also observed in sod1 linked fals patients [ 12 ]. |
| 31395 | COX8B | cytochrome c oxidase, subunit 8B pseudogene | cytochrome c oxidase | 1.0 | as a chain of consequent events modulating extracellular transport uptake intracellular delivery from chaperones e.g copper chaperone for sod1 ccs cox17 and atx1 to specific targets such as sod1 and cytochrome c oxidase and/or storage in copper scavenging systems such as gsh and metallothioneins [ 72 ]. |
| 2295 | CP | ceruloplasmin (ferroxidase) | ceruloplasmin | 1.0 | one link between cu and fe metabolism is represented by the enzyme ceruloplasmin cp the copper protein of the plasma. |
| 2295 | CP | ceruloplasmin (ferroxidase) | ferroxidase | 1.0 | cp is an enzyme with very efficient ferroxidase activity [ 41 ] that is able to oxidise fe ii to fe iii conveying four electrons to oxygen in a single step: thus water is produced and iron can enter its transport and deposit pathway via incorporat |
| 11740 | TF | transferrin | transferrin | 1.0 | [ 41 ] that is able to oxidise fe ii to fe iii conveying four electrons to oxygen in a single step: thus water is produced and iron can enter its transport and deposit pathway via incorporation into transferrin. |
| 11763 | TFRC | transferrin receptor (p90, CD71) | transferrin receptor | 1.0 | if the ire is located on the 3_amp_#x2032; untranslated region of the mrna the binding of irp usually causes an up regulation of the coded protein as for example for the transferrin receptor [ 28 ]. |
| 9605 | PTGS2 | prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase) | cox2 | 1.0 | nf _amp_#x3ba;b modulates the expression of several proteins such as nitric oxide synthase nos [ 93 ] and cox2 [ 70 ] that might be involved in mechanisms of inflammation mediated neurodegeneration and be crucial in the pathogenesis of als. |
| 7873 | NOS2A | nitric oxide synthase 2A (inducible, hepatocytes) | nitric oxide synthase | 1.0 | nf _amp_#x3ba;b modulates the expression of several proteins such as nitric oxide synthase nos [ 93 ] and cox2 [ 70 ] that might be involved in mechanisms of inflammation mediated neurodegeneration and be crucial in the pathogenesis of als. |
| 9605 | PTGS2 | prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase) | cox2 | 1.0 | indeed cox2 and nos activity are dramatically increased in post mortem spinal cord samples from sporadic als patients and in astrocytes from fals mice [ 2 and 15 ]. |
| 9605 | PTGS2 | prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase) | cox2 | 1.0 | increased levels of cox2 and of the pro inflammatory prostaglandin pge2 were found in the cerebrospinal fluid from als patients [ 3 ]. |
| 9605 | PTGS2 | prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase) | cox2 | 1.0 | treatment with a selective cox2 inhibitor markedly inhibits production of pge2 in the spinal cord of als mice protecting motor neurones and significantly prolonging survival [ 23 ]. |