)| PMID |
14739060 ( ) |
|---|---|
| Title | Neurodegenerative diseases and oxidative stress. |
| Abstract | Oxidative stress is now recognized as accountable for redox regulation involving reactive oxygen species (ROS) and reactive nitrogen species (RNS). Its role is pivotal for the modulation of critical cellular functions, notably for neurons astrocytes and microglia, such as apoptosis program activation, and ion transport, calcium mobilization, involved in excitotoxicity. Excitotoxicity and apoptosis are the two main causes of neuronal death. The role of mitochondria in apoptosis is crucial. Multiple apoptotic pathways emanate from the mitochondria. The respiratory chain of mitochondria that by oxidative phosphorylation, is the fount of cellular energy, i.e. ATP synthesis, is responsible for most of ROS and notably the first produced, superoxide anion (O(2)(;-)). Mitochondrial dysfunction, i.e. cell energy impairment, apoptosis and overproduction of ROS, is a final common pathogenic mechanism in aging and in neurodegenerative disease such as Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). Nitric oxide (NO(;)), an RNS, which can be produced by three isoforms of NO-synthase in brain, plays a prominent role. The research on the genetics of inherited forms notably ALS, AD, PD, has improved our understanding of the pathobiology of the sporadic forms of neurodegenerative diseases or of aging of the brain. ROS and RNS, i.e. oxidative stress, are not the origin of neuronal death. The cascade of events that leads to neurons, death is complex. In addition to mitochondrial dysfunction (apoptosis), excitotoxicity, oxidative stress (inflammation), the mechanisms from gene to disease involve also protein misfolding leading to aggregates and proteasome dysfunction on ubiquinited material. Pitie-Salpetriere, 47, boulevard de l'Hopital, 75651 cedex 13, Paris, France. emerit@wanadoo.fr |
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)) | 12 | SOD1 | SOD | |
| 6893 | MAPT | microtubule-associated protein tau | 5 | tau protein | |
| 620 | APP | amyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease) | 3 | amyloid | |
| 19986 | CYCS | cytochrome c, somatic | 3 | cytochrome c | |
| 10417 | RPS27A | ribosomal protein S27a | 3 | ubiquitin | |
| 2244 | COQ7 | coenzyme Q7 homolog, ubiquinone (yeast) | 3 | coenzyme q | |
| 7872 | NOS1 | nitric oxide synthase 1 (neuronal) | 3 | nNOS | |
| 4341 | GLUL | glutamate-ammonia ligase (glutamine synthetase) | 2 | glutamine synthetase | |
| 26515 | COQ10A | coenzyme Q10 homolog A (S. cerevisiae) | 2 | Q10 | |
| 7876 | NOS3 | nitric oxide synthase 3 (endothelial cell) | 2 | eNOS | |
| 1499 | CASP1 | caspase 1, apoptosis-related cysteine peptidase (interleukin 1, beta, convertase) | 2 | caspase 1 | |
| 7873 | NOS2A | nitric oxide synthase 2A (inducible, hepatocytes) | 2 | iNOS | |
| 613 | APOE | apolipoprotein E | 2 | APOE | |
| 9509 | PSEN2 | presenilin 2 (Alzheimer disease 4) | 2 | PSEN2 | presenilin 2 | |
| 990 | BCL2 | B-cell CLL/lymphoma 2 | 2 | bcl2 | Bcl2 | |
| 2773 | DFFB | DNA fragmentation factor, 40kDa, beta polypeptide (caspase-activated DNase) | 2 | caspase activated dnase | |
| 9508 | PSEN1 | presenilin 1 (Alzheimer disease 3) | 2 | PSEN1 | presenilin 1 | |
| 118 | ACO2 | aconitase 2, mitochondrial | 1 | aconitase | |
| 11180 | SOD2 | superoxide dismutase 2, mitochondrial | 1 | MnSOD | |
| 576 | APAF1 | apoptotic peptidase activating factor 1 | 1 | Apaf1 | |
| 9461 | PRPH | peripherin | 1 | peripherin | |
| 6871 | MAPK1 | mitogen-activated protein kinase 1 | 1 | MAP | |
| 4851 | HTT | huntingtin | 1 | huntingtin | |
| 21528 | DIABLO | diablo homolog (Drosophila) | 1 | Smac | |
| 11892 | TNF | tumor necrosis factor (TNF superfamily, member 2) | 1 | TNF | |
| 3346 | ENDOG | endonuclease G | 1 | endonuclease g | |
| 4571 | GRIA1 | glutamate receptor, ionotropic, AMPA 1 | 1 | glutamate receptor | |
| 12805 | XDH | xanthine dehydrogenase | 1 | xanthine oxidase | |
| 21148 | RNF123 | ring finger protein 123 | 1 | ubiquitin ligase | |
| 4331 | GLS | glutaminase | 1 | glutaminase | |
| 5991 | IL1A | interleukin 1, alpha | 1 | IL1 | |
| 9393 | PRKCA | protein kinase C, alpha | 1 | protein kinase c | |
| 8768 | AIFM1 | apoptosis-inducing factor, mitochondrion-associated, 1 | 1 | apoptosis inducing factor | |
Targets by SciMiner Full list
| HUGO ID | Symbol | Name | ActualStr | Score | FlankingText |
|---|---|---|---|---|---|
| 7872 | NOS1 | nitric oxide synthase 1 (neuronal) | nNOS | 1.9 | account for NO production and include neuronal NO synthase (nNOS; nNOS type I inducible NO synthase (iNOS; iNOS typeII which is |
| 7873 | NOS2A | nitric oxide synthase 2A (inducible, hepatocytes) | iNOS | 1.9 | NO synthase (nNOS; nNOS type I inducible NO synthase (iNOS; iNOS typeII which is produced in very large amounts by activated |
| 7876 | NOS3 | nitric oxide synthase 3 (endothelial cell) | eNOS | 1.9 | by activated microglia (macrophages), macrophages and endothelial NO synthase (eNOS; eNOS type III In the CNS nNOS whose expression is regulated |
| 7872 | NOS1 | nitric oxide synthase 1 (neuronal) | nNOS | 1.9 | endothelial NO synthase (eNOS; eNOS type III In the CNS nNOS whose expression is regulated by both physiological and pathophysiological stimuli |
| 7873 | NOS2A | nitric oxide synthase 2A (inducible, hepatocytes) | iNOS | 1.9 | in pathologic conditions especially NO coming from activated microglia (iNOS) iNOS or and from endothelial cells (eNOS) eNOS |
| 7876 | NOS3 | nitric oxide synthase 3 (endothelial cell) | eNOS | 1.9 | activated microglia (iNOS) iNOS or and from endothelial cells (eNOS) eNOS |
| 6871 | MAPK1 | mitogen-activated protein kinase 1 | MAP | 0.3 | for neurons astrocytes and microglia such as mitogene-activated protein (MAP) MAP kinase cascade activation ion transport calcium mobilization and apoptosis program |
| 7872 | NOS1 | nitric oxide synthase 1 (neuronal) | nNOS | 1.9 | series of enzymes including protein kinase C proteases phosphatases phospholipases nNOS and xanthine oxidase 32 |
| 990 | BCL2 | B-cell CLL/lymphoma 2 | Bcl2 | 0.0 | the release of apoptogenic mitochondrial mediators _amp_#x2022 Pro-apoptotic members of Bcl2 family _amp_#x2022 elevated levels of intra-cellular calcium such as that |
| 21528 | DIABLO | diablo homolog (Drosophila) | Smac | 1.3 | the mitochondria into cytoplasm trigger the caspase chain _amp_#x2022 Smac/Diablo Smac Diablo binds to inhibitors of activated caspases and causes further |
| 576 | APAF1 | apoptotic peptidase activating factor 1 | Apaf1 | 0.3 | Cytochrome c and the cytosolic factor Apaf1 activate the caspases while apoptosis-initiating factor and caspase activated DNase |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD | 1.3 | of motor neurons caused by a missense mutation of CuZn SOD (SOD1) SOD1 is an illustration of how these mechanisms can |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.1 | neurons caused by a missense mutation of CuZn SOD (SOD1) SOD1 is an illustration of how these mechanisms can lead to |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.1 | In transgenic mice expressing the human mutant SOD1 gene syndrome develops with many features of ALS including specific |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.1 | to compare the evolution for motor neurons degeneration in mutant SOD1 transgenic mouse with non-transgenic mouse and normal human SOD1 transgenic |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.1 | mutant SOD1 transgenic mouse with non-transgenic mouse and normal human SOD1 transgenic mouse 46 50 47 48 and 49 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.1 | The toxicity of mutant SOD1 seems to be due to a gain of function of |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.1 | It is also conceivable mutant SOD1 denatures more quickly in vivo than the normal form and |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.1 | Oxidative stress may be involved in misfolding of mutant SOD1 to form abnormal protein aggregates found as early as 1_amp_#xa0 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.1 | disorganization of intermediate filaments could be due also to mutant SOD1 induced toxicity as their proteins are vulnerable to oxidative damage |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.1 | in patients with sporadic ALS and in transgenic mice with SOD1 mutations |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD | 1.3 | of ubiquinated cytoplasmic inclusion bodies some of which contain aggregated SOD 46 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 2.1 | The studies on mutant SOD1 transgenic mice 46 and 63 revealed an up-regulation of gene |
| 620 | APP | amyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease) | amyloid | 1.0 | forms missense mutation have been identified for gene encoding _amp_#x3b2 -amyloid precursor protein as well as presenilin 1 (PSEN1) PSEN1 and |
| 9508 | PSEN1 | presenilin 1 (Alzheimer disease 3) | PSEN1 | 0.9 | _amp_#x3b2 -amyloid precursor protein as well as presenilin 1 (PSEN1) PSEN1 and presenilin 2 (PSEN2) PSEN2 |
| 9509 | PSEN2 | presenilin 2 (Alzheimer disease 4) | PSEN2 | 0.9 | well as presenilin 1 (PSEN1) PSEN1 and presenilin 2 (PSEN2) PSEN2 |
| 6893 | MAPT | microtubule-associated protein tau | tau | 1.9 | gene for _amp_#x3b1 2 -macrogobulin and perhaps the gene for tau protein and other factors including environmental contributions and occurrence by |
| 613 | APOE | apolipoprotein E | APOE | 0.0 | a complex interaction among multiple predisposing genes such as variant APOE the gene for _amp_#x3b1 2 -macrogobulin and perhaps the gene |
| 6893 | MAPT | microtubule-associated protein tau | tau | 1.9 | tangles and senile plaques are both aggregation of proteins microtubular tau protein for the former accumulation of several aggregated proteins (_amp_#x3b2;-amyloid, |
| 620 | APP | amyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease) | amyloid | 1.0 | for the former accumulation of several aggregated proteins (_amp_#x3b2;-amyloid, _amp_#x3b2 -amyloid especially its toxic form A_amp_#x3b2 42 APOE 43 hyperphosphorylated tau |
| 6893 | MAPT | microtubule-associated protein tau | tau | 1.9 | -amyloid especially its toxic form A_amp_#x3b2 42 APOE 43 hyperphosphorylated tau ubiquitin presenilin 1_amp_#xa0 and 2 with an inflammatory reaction around |
| 620 | APP | amyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease) | amyloid | 1.0 | 2 with an inflammatory reaction around the deposit of _amp_#x3b2 -amyloid for the latter 38 |
| 613 | APOE | apolipoprotein E | APOE | 0.0 | proteins (_amp_#x3b2;-amyloid, _amp_#x3b2 -amyloid especially its toxic form A_amp_#x3b2 42 APOE 43 hyperphosphorylated tau ubiquitin presenilin 1_amp_#xa0 and 2 with an |
| 26515 | COQ10A | coenzyme Q10 homolog A (S. cerevisiae) | Q10 | 0.9 | a controlled trial in early PD oral treatment with coenzyme Q10 has slowed the progressive deterioration 56 and in aged mice |
| 118 | ACO2 | aconitase 2, mitochondrial | aconitase | 1.3 | may prevent the formation of Fe/S Fe S in mitochondrial aconitase and in complex I 20 |
| 26515 | COQ10A | coenzyme Q10 homolog A (S. cerevisiae) | Q10 | 0.9 | affected sisters clinical and biochemical abnormalities improved remarkably with coenzyme Q10 supplementation 59 |
| 11892 | TNF | tumor necrosis factor (TNF superfamily, member 2) | TNF | 0.3 | amplification resulting in production of neurotoxins such as cytokine (TNF, TNF IL1 eicosanoides ROS and RNS 9 and 13 |
| 5991 | IL1A | interleukin 1, alpha | IL1 | 0.2 | resulting in production of neurotoxins such as cytokine (TNF, TNF IL1 eicosanoides ROS and RNS 9 and 13 |
| 11180 | SOD2 | superoxide dismutase 2, mitochondrial | MnSOD | 1.8 | Tat protein decreases GSH and down regulate MnSOD gene expression leading to oxidative stress 16 |
| 9393 | PRKCA | protein kinase C, alpha | protein kinase c | 1.0 | neuronal increases in calcium can activate a series of enzymes including protein kinase c proteases phosphatases phospholipases nnos and xanthine oxidase [ 32 ]. |
| 12805 | XDH | xanthine dehydrogenase | xanthine oxidase | 1.0 | neuronal increases in calcium can activate a series of enzymes including protein kinase c proteases phosphatases phospholipases nnos and xanthine oxidase [ 32 ]. |
| 4341 | GLUL | glutamate-ammonia ligase (glutamine synthetase) | glutamine synthetase | 1.0 | astrocytes take up glutamate convert it to glutamine through the action of glutamine synthetase an enzyme requiring atp and then release it for uptake by neurons. |
| 4331 | GLS | glutaminase | glutaminase | 1.0 | neurons then convert glutamine back to glutamate through the action of glutaminase. |
| 4341 | GLUL | glutamate-ammonia ligase (glutamine synthetase) | glutamine synthetase | 1.0 | this cycle can be disrupted by inhibitors of glutamine synthetase an enzyme which can be easily damaged by oxidative stress [ 31 ]. |
| 4571 | GRIA1 | glutamate receptor, ionotropic, AMPA 1 | glutamate receptor | 1.0 | finally excessive response to glutamate receptor mediated stimulation occur intra cellularly [ 32 ]. |
| 990 | BCL2 | B-cell CLL/lymphoma 2 | bcl2 | 1.0 | three main signals cause the release of apoptogenic mitochondrial mediators: _amp_#x2022; pro apoptotic members of bcl2 family _amp_#x2022; elevated levels of intra cellular calcium such as that triggered by excitotoxicity _amp_#x2022; elevated levels of ros_amp_#x2013;rns |
| 8768 | AIFM1 | apoptosis-inducing factor, mitochondrion-associated, 1 | apoptosis inducing factor | 1.0 | hen it is released from the mitochondria into cytoplasm trigger the caspase chain _amp_#x2022; smac/diablo binds to inhibitors of activated caspases and causes further caspase activation _amp_#x2022; apoptosis inducing factor and endonuclease g mediate caspase independent cell death pathways |
| 3346 | ENDOG | endonuclease G | endonuclease g | 1.0 | tochondria into cytoplasm trigger the caspase chain _amp_#x2022; smac/diablo binds to inhibitors of activated caspases and causes further caspase activation _amp_#x2022; apoptosis inducing factor and endonuclease g mediate caspase independent cell death pathways |
| 19986 | CYCS | cytochrome c, somatic | cytochrome c | 1.0 | _amp_#x2022; cytochrome c a member of the mitochondrial electron chain required for the generation of atp when it is released from the mitochondria into cytoplasm trigger the caspase chain _amp_#x2022; smac/diablo binds to in |
| 2773 | DFFB | DNA fragmentation factor, 40kDa, beta polypeptide (caspase-activated DNase) | caspase activated dnase | 1.0 | he collapse of trans membrane electrochemical gradient the loss of matrix solutes the swelling of mitochondria causing the release of cytochrome c procapases 2 3 and 9 apoptosis initiating factor and caspase activated dnase. |
| 19986 | CYCS | cytochrome c, somatic | cytochrome c | 1.0 | this results in the collapse of trans membrane electrochemical gradient the loss of matrix solutes the swelling of mitochondria causing the release of cytochrome c procapases 2 3 and 9 apoptosis initiating factor and caspase activated dnase. |
| 2773 | DFFB | DNA fragmentation factor, 40kDa, beta polypeptide (caspase-activated DNase) | caspase activated dnase | 1.0 | cytochrome c and the cytosolic factor apaf1 activate the caspases while apoptosis initiating factor and caspase activated dnase move to the nucleus initiating apoptosis or programmed cell death [ 27 ]. |
| 19986 | CYCS | cytochrome c, somatic | cytochrome c | 1.0 | cytochrome c and the cytosolic factor apaf1 activate the caspases while apoptosis initiating factor and caspase activated dnase move to the nucleus initiating apoptosis or programmed cell death [ 27 ]. |
| 10417 | RPS27A | ribosomal protein S27a | ubiquitin | 1.0 | g93a transgenic mouse [ 46 50 47 48 and 49 ]. _amp_#x2022; protein misfolding and aggregates: for example of a_amp_#x3b2; 42 for ad [ 43 ]. _amp_#x2022; proteasome dysfunction on ubiquinited material ubiquitin forms covalent bonds with other protein in order to mark them for degradation by an atp dependent non lysosomial proteolytic system i.e proteasome . _amp_#x2022; oxidative stress mitochondria dysfunc |
| 9461 | PRPH | peripherin | peripherin | 1.0 | another intermediate filament peripherin is found in neuronal inclusions in patients with sporadic als and in transgenic mice with sod1 mutations. |
| 1499 | CASP1 | caspase 1, apoptosis-related cysteine peptidase (interleukin 1, beta, convertase) | caspase 1 | 1.0 | the involvement of mitochondria and apoptosis in neuronal death is too revealed by a prolonged period of neuronal caspase activation especially caspase 1 [ 17 ]. |
| 1499 | CASP1 | caspase 1, apoptosis-related cysteine peptidase (interleukin 1, beta, convertase) | caspase 1 | 1.0 | ice [ 46 and 63 ] revealed an up regulation of gene related to an inflammatory process such as tnf_amp_#x3b1; gene resulting in glial activation together with change in apoptosis related gene such as caspase 1. |
| 9508 | PSEN1 | presenilin 1 (Alzheimer disease 3) | presenilin 1 | 1.0 | in familial forms missense mutation have been identified for gene encoding _amp_#x3b2; amyloid precursor protein as well as presenilin 1 psen1 and presenilin 2 psen2 . |
| 9509 | PSEN2 | presenilin 2 (Alzheimer disease 4) | presenilin 2 | 1.0 | in familial forms missense mutation have been identified for gene encoding _amp_#x3b2; amyloid precursor protein as well as presenilin 1 psen1 and presenilin 2 psen2 . |
| 6893 | MAPT | microtubule-associated protein tau | tau protein | 1.0 | the sporadic forms are thought to result from a complex interaction among multiple predisposing genes such as variant apoe the gene for _amp_#x3b1; 2 macrogobulin and perhaps the gene for tau protein and other factors including environmental contributions and occurrence by chance [ 45 and 58 ]. |
| 10417 | RPS27A | ribosomal protein S27a | ubiquitin | 1.0 | tion of proteins: microtubular tau protein for the former accumulation of several aggregated proteins _amp_#x3b2; amyloid especially its toxic form a_amp_#x3b2; 42 apoe [ 43 ] hyperphosphorylated tau ubiquitin presenilin 1_amp_#xa0;and 2 with an inflammatory reaction around the deposit of _amp_#x3b2; amyloid for the latter [ 38 ]. |
| 6893 | MAPT | microtubule-associated protein tau | tau protein | 1.0 | the neuropathological hallmarks neurofibrillary tangles and senile plaques are both aggregation of proteins: microtubular tau protein for the former accumulation of several aggregated proteins _amp_#x3b2; amyloid especially its toxic form a_amp_#x3b2; 42 apoe [ 43 ] hyperphosphorylated tau ubiquitin presenilin 1_amp_#xa0;and 2 with |
| 21148 | RNF123 | ring finger protein 123 | ubiquitin ligase | 1.0 | parkin is one member of the family of ubiquitin ligase responsible for ubiquination a process tagging proteins for degradation through proteosomal pathway. |
| 4851 | HTT | huntingtin | huntingtin | 1.0 | the increased number in gag repeats in the mutant gene are expressed as an elongated huntingtin protein [ 38 ]. |
| 10417 | RPS27A | ribosomal protein S27a | ubiquitin | 1.0 | as demonstrated in transgenic mouse this abnormal protein is cleaved to fragments conjugated with ubiquitin; which aggregate forming neuronal intra nuclear inclusions. |
| 2244 | COQ7 | coenzyme Q7 homolog, ubiquinone (yeast) | coenzyme q | 1.0 | primary coenzyme q deficiency cause a mitochondrial encephalomyopathy that is responsive to coenzyme q administration [ 44 ]. |
| 2244 | COQ7 | coenzyme Q7 homolog, ubiquinone (yeast) | coenzyme q | 1.0 | clinical trials are underway to test inhibitors of apoptosis such as minocycline [ 17 ] coenzyme q in pd [ 56 ] and many others using so called antioxidants despite disappointing results obtained [ 51 and 52 ]. |
| 2244 | COQ7 | coenzyme Q7 homolog, ubiquinone (yeast) | coenzyme q | 1.0 | then the antioxidant defenses: vitamins a e c selenium food rich in vegetables and fruits and perhaps by using mitochondrial cofactors such as l carnitine r _amp_#x3b1; lipoic acid [ 35 ] riboflavine coenzyme q etc. |