)| PMID |
10643818 ( ) |
|---|---|
| Title | Final common pathways in neurodegenerative diseases: regulatory role of the glutathione cycle. |
| Abstract | Attempts to unify diverse mechanisms of neurotoxicity have led to the concept of final common pathways which characterize frequently occurring cellular responses to disruption of homeostasis. The clinical presentation and common patho-biochemistry of reactive oxygen intermediates of Guam's disease have suggested that such pathways may be operative in three major neurodegenerative disorders: Alzheimer's dementia, amyotrophic lateral sclerosis and Parkinson's disease. A candidate-signaling pathway in this regard is characterized by the cascade arachidonic acid/HPETE/*OH/cGMP followed by activation of cGMP-dependent kinase and phosphorylation of NF-kB proteins and possibly CREB. This sequence may lead to apoptosis as well as long-term potentiation and memory and constitutes a biochemical correlate to excitotoxicity. The predominant control of *OH release from HPETE, a checkpoint in this pathway, is exerted by the glutathione cycle, a central biochemical process that is also intimately associated with the synthesis of the neurotransmitters glutamate and GABA and is connected to energy metabolism. Modifications in the activity of the glutathione cycle may provide treatment options. School, Boston, MA 02115, USA. georg_weber@dfci.harvard.edu |
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 |
|---|---|---|---|---|
| 620 | APP | amyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease) | 25 | APP | amyloid | amyloid-dependent | |
| 9509 | PSEN2 | presenilin 2 (Alzheimer disease 4) | 6 | presenilin 2 | STM2 | PS2 | |
| 613 | APOE | apolipoprotein E | 5 | apolipoprotein e | ApoE | |
| 7794 | NFKB1 | nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (p105) | 4 | NF-kB | |
| 11919 | CD40 | CD40 molecule, TNF receptor superfamily member 5 | 3 | p50 | |
| 2345 | CREB1 | cAMP responsive element binding protein 1 | 3 | CREB | |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | 3 | superoxide dismutase | |
| 9393 | PRKCA | protein kinase C, alpha | 3 | protein kinase c | |
| 4250 | GGT1 | gamma-glutamyltransferase 1 | 2 | glutamyl transpeptidase | |
| 9508 | PSEN1 | presenilin 1 (Alzheimer disease 3) | 2 | PS1 | presenilin 1 | |
| 429 | ALOX12 | arachidonate 12-lipoxygenase | 2 | 12 lipoxygenase | |
| 11920 | FAS | Fas (TNF receptor superfamily, member 6) | 2 | Fas | fas antigen | |
| 1848 | CEL | carboxyl ester lipase (bile salt-stimulated lipase) | 1 | FAP | |
| 4983 | HMGB1 | high-mobility group box 1 | 1 | amphoterin | |
| 5013 | HMOX1 | heme oxygenase (decycling) 1 | 1 | heme oxygenase 1 | |
| 9065 | PLCG1 | phospholipase C, gamma 1 | 1 | PLC | |
| 1516 | CAT | catalase | 1 | catalase | |
| 6207 | JUP | junction plakoglobin | 1 | catenin | |
| 26333 | SRFBP1 | serum response factor binding protein 1 | 1 | p49 | |
| 4553 | GPX1 | glutathione peroxidase 1 | 1 | cellular glutathione peroxidase | |
| 15917 | PLCB1 | phospholipase C, beta 1 (phosphoinositide-specific) | 1 | phospholipase c | |
| 3796 | FOS | v-fos FBJ murine osteosarcoma viral oncogene homolog | 1 | c fos | |
| 4624 | GSS | glutathione synthetase | 1 | glutathione synthetase | |
| 4623 | GSR | glutathione reductase | 1 | glutathione reductase | |
| 7872 | NOS1 | nitric oxide synthase 1 (neuronal) | 1 | NOS | |
Targets by SciMiner Full list
| HUGO ID | Symbol | Name | ActualStr | Score | FlankingText |
|---|---|---|---|---|---|
| 7794 | NFKB1 | nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (p105) | NF-kB | 1.3 | cGMP followed by activation of cGMP-dependent kinase and phosphorylation of NF-kB proteins and possibly CREB |
| 2345 | CREB1 | cAMP responsive element binding protein 1 | CREB | 1.3 | of cGMP-dependent kinase and phosphorylation of NF-kB proteins and possibly CREB |
| 2345 | CREB1 | cAMP responsive element binding protein 1 | CREB | 1.3 | The transcription factor CREB is a likely substrate for cGMP-dependent kinase that has been |
| 11920 | FAS | Fas (TNF receptor superfamily, member 6) | Fas | 0.6 | TNF-receptor-dependent signaling 9 10 and 11 and engagement of the Fas antigen 12 |
| 7794 | NFKB1 | nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (p105) | NF-kB | 1.3 | nervous system expression of heme oxygenase-1 and nuclear localization of NF-kB p50 13 are intimately associated with the outlined pathway because |
| 11919 | CD40 | CD40 molecule, TNF receptor superfamily member 5 | p50 | 1.1 | system expression of heme oxygenase-1 and nuclear localization of NF-kB p50 13 are intimately associated with the outlined pathway because heme |
| 7794 | NFKB1 | nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (p105) | NF-kB | 1.3 | because heme oxygenase-1 may activate cGMP kinase 7 while the NF-kB proteins p50 and p49 are substrates for this enzyme (Weber, |
| 11919 | CD40 | CD40 molecule, TNF receptor superfamily member 5 | p50 | 1.1 | oxygenase-1 may activate cGMP kinase 7 while the NF-kB proteins p50 and p49 are substrates for this enzyme (Weber, Weber unpublished |
| 26333 | SRFBP1 | serum response factor binding protein 1 | p49 | 0.6 | activate cGMP kinase 7 while the NF-kB proteins p50 and p49 are substrates for this enzyme (Weber, Weber unpublished results |
| 2345 | CREB1 | cAMP responsive element binding protein 1 | CREB | 1.3 | also induces expression of c-Fos possibly via activation of SRE CREB or FAP 14 |
| 1848 | CEL | carboxyl ester lipase (bile salt-stimulated lipase) | FAP | 1.0 | expression of c-Fos possibly via activation of SRE CREB or FAP 14 |
| 620 | APP | amyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease) | amyloid | 1.8 | factors for familial Alzheimer's disease have been localized to the amyloid precursor protein apolipoprotein E presenilin 1 and presenilin 2 genes |
| 620 | APP | amyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease) | amyloid | 1.8 | mechanisms of action of these diverse molecules include regulation of amyloid production and of the metabolism of reactive oxygen intermediates so |
| 620 | APP | amyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease) | amyloid | 1.8 | that malfunctioning of these gene products causes elevated generation of amyloid _amp_#x3b2 protein and of reactive oxygen species ( Table 1 |
| 620 | APP | amyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease) | amyloid | 1.8 | stress may sensitize neurons to the apoptotic signals induced by amyloid (see see later creating a double burden |
| 9508 | PSEN1 | presenilin 1 (Alzheimer disease 3) | PS1 | 0.9 | Presenilins (PS1 PS1 and PS2 contribute to the regulation of apoptosis with the |
| 9509 | PSEN2 | presenilin 2 (Alzheimer disease 4) | PS2 | 2.4 | Presenilins (PS1 PS1 and PS2 contribute to the regulation of apoptosis with the |
| 9509 | PSEN2 | presenilin 2 (Alzheimer disease 4) | PS2 | 2.4 | Presenilins (PS1 PS1 and PS2 contribute to the regulation of apoptosis with the wild-type of |
| 9509 | PSEN2 | presenilin 2 (Alzheimer disease 4) | STM2 | 3.2 | the regulation of apoptosis with the wild-type of Alzheimer's gene STM2 (PS2) PS2 exerting anti-apoptotic effects 16 |
| 9509 | PSEN2 | presenilin 2 (Alzheimer disease 4) | PS2 | 2.4 | of apoptosis with the wild-type of Alzheimer's gene STM2 (PS2) PS2 exerting anti-apoptotic effects 16 |
| 620 | APP | amyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease) | amyloid | 1.8 | -catenin can activate _amp_#x3b3 -secretase the enzyme that releases the amyloid fragment A_amp_#x3b2;(1-42), A_amp_#x3b2 1-42 with a consequent increase in the |
| 620 | APP | amyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease) | amyloid | 1.8 | A_amp_#x3b2;(1-42), A_amp_#x3b2 1-42 with a consequent increase in the excreted amyloid _amp_#x3b2 |
| 613 | APOE | apolipoprotein E | ApoE | 1.3 | Apolipoprotein E (ApoE) ApoE protects neurons from hydrogen peroxide toxicity and binds specific metal |
| 620 | APP | amyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease) | amyloid | 1.8 | Apolipoprotein E may also protect from _amp_#x3b2 -amyloid peptide toxicity by binding to amyloid _amp_#x3b2 and under certain |
| 620 | APP | amyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease) | amyloid | 1.8 | also protect from _amp_#x3b2 -amyloid peptide toxicity by binding to amyloid _amp_#x3b2 and under certain circumstances acting as kinetic inhibitor of |
| 620 | APP | amyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease) | amyloid | 1.8 | _amp_#x3b2 and under certain circumstances acting as kinetic inhibitor of amyloid formation 18 |
| 620 | APP | amyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease) | amyloid | 1.8 | The major proteinaceous component of plaques is _amp_#x3b2 -amyloid the abnormal cleavage product of the amyloid precursor protein (APP) |
| 620 | APP | amyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease) | amyloid | 1.8 | plaques is _amp_#x3b2 -amyloid the abnormal cleavage product of the amyloid precursor protein (APP) APP |
| 620 | APP | amyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease) | APP | 0.3 | the abnormal cleavage product of the amyloid precursor protein (APP) APP |
| 620 | APP | amyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease) | amyloid | 1.8 | Various metals can bind to amyloid precursor protein and influence its conformation stability and homophilic interactions |
| 620 | APP | amyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease) | APP | 0.3 | APP may bind copper and catalyze a redox reaction that reduces |
| 620 | APP | amyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease) | amyloid | 1.8 | Cu I and gives rise to cystine formation in the amyloid precursor protein |
| 620 | APP | amyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease) | amyloid | 1.8 | the binding of zinc which can lead to precipitation of amyloid protein 20 may also be associated with changes in the |
| 620 | APP | amyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease) | amyloid | 1.8 | While the function of amyloid precursor protein as a free radical generator may contribute to |
| 620 | APP | amyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease) | amyloid | 1.8 | generator may contribute to affecting neuron viability the concentrations of amyloid _amp_#x3b2 required to generate free radicals are in general moderately |
| 620 | APP | amyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease) | amyloid | 1.8 | Furthermore the accumulation of intercellular masses of amyloid in contrast to the soluble molecules is not suitable to |
| 620 | APP | amyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease) | amyloid | 1.8 | An alternative mechanism by which amyloid _amp_#x3b2 may cause oxidative stress in neurons as well as |
| 7794 | NFKB1 | nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (p105) | NF-kB | 1.3 | RAGE may increase lipid peroxidation as well as activation of NF-kB p50 22 |
| 11919 | CD40 | CD40 molecule, TNF receptor superfamily member 5 | p50 | 1.1 | may increase lipid peroxidation as well as activation of NF-kB p50 22 |
| 620 | APP | amyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease) | amyloid | 1.8 | -acetylcysteine 23 and inhibition of lipoxygenase protects hippocampal neurons from amyloid _amp_#x3b2 toxicity 24 |
| 620 | APP | amyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease) | amyloid | 1.8 | The oxidative stress generated via production of free radicals by amyloid or via amyloid-dependent signaling can be increased by the common |
| 620 | APP | amyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease) | amyloid-dependent | 1.0 | generated via production of free radicals by amyloid or via amyloid-dependent signaling can be increased by the common risk factors through |
| 9065 | PLCG1 | phospholipase C, gamma 1 | PLC | 0.6 | PLA 2 phopholipase A 2 PLC phospholipase C DAG diacyl glycerol AA arachidonic acid PKC protein |
| 7872 | NOS1 | nitric oxide synthase 1 (neuronal) | NOS | 0.9 | AA arachidonic acid PKC protein kinase C GPX glutathione peroxidase NOS NO synthetase LTP long-term potentiation |
| 620 | APP | amyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease) | amyloid | 1.8 | affected in Alzheimer's disease share two common mechanisms control of amyloid _amp_#x3b2 secretion and of oxidative stress leading to apoptosis |
| 620 | APP | amyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease) | amyloid | 1.8 | The mechanism of apoptosis induction by amyloid _amp_#x3b2 converges with the signal transduction cascade that mediates long-term |
| 9393 | PRKCA | protein kinase C, alpha | protein kinase c | 1.0 | this pathway is relevant for induction of long term potentiation while protein kinase c pkc causes maintenance of long term potentiation and protein kinase c can be induced by calcium arachidonate and reactive oxygen species fig 1b . |
| 429 | ALOX12 | arachidonate 12-lipoxygenase | 12 lipoxygenase | 1.0 | in functional synergism 12 lipoxygenase is directly inhibited by reduced glutathione [ 5 ]. |
| 11920 | FAS | Fas (TNF receptor superfamily, member 6) | fas antigen | 1.0 | erm potentiation has been attributed to programmed cell death in t lymphocytes [ 7 and 8 ] and has been inferred from studies of tnf receptor dependent signaling [ 9 10 and 11 ] and engagement of the fas antigen [ 12 ]. |
| 5013 | HMOX1 | heme oxygenase (decycling) 1 | heme oxygenase 1 | 1.0 | two markers of oxidative stress in the central nervous system expression of heme oxygenase 1 and nuclear localization of nf kb p50 [ 13 ] are intimately associated with the outlined pathway because heme oxygenase 1 may activate cgmp kinase [ 7 ] while the nf kb proteins p50 and p49 are substrates for this enzyme weber unpublished results . |
| 3796 | FOS | v-fos FBJ murine osteosarcoma viral oncogene homolog | c fos | 1.0 | cyclic gmp dependent kinase also induces expression of c fos possibly via activation of sre creb or fap [ 14 ]. |
| 4623 | GSR | glutathione reductase | glutathione reductase | 1.0 | this is accomplished by the redox cycle catalyzed by glutathione peroxidase and glutathione reductase which can scavenge reactive oxygen intermediates including hpete during glutathione oxidation. |
| 429 | ALOX12 | arachidonate 12-lipoxygenase | 12 lipoxygenase | 1.0 | in conjunction with direct inhibition of 12 lipoxygenase by glutathione [ 5 ] this mechanism may account for protection from excitotoxicity. |
| 613 | APOE | apolipoprotein E | apolipoprotein e | 1.0 | known genetic risk factors for familial alzheimer's disease have been localized to the amyloid precursor protein apolipoprotein e presenilin 1 and presenilin 2 genes. |
| 9508 | PSEN1 | presenilin 1 (Alzheimer disease 3) | presenilin 1 | 1.0 | known genetic risk factors for familial alzheimer's disease have been localized to the amyloid precursor protein apolipoprotein e presenilin 1 and presenilin 2 genes. |
| 9509 | PSEN2 | presenilin 2 (Alzheimer disease 4) | presenilin 2 | 1.0 | known genetic risk factors for familial alzheimer's disease have been localized to the amyloid precursor protein apolipoprotein e presenilin 1 and presenilin 2 genes. |
| 9509 | PSEN2 | presenilin 2 (Alzheimer disease 4) | presenilin 2 | 1.0 | during apoptosis they may be cleaved distal to their normal cleavage sites and a mutation in presenilin 2 that is related to familial alzheimer's disease favors this alternative cleavage which may either directly enhance apoptosis or diminish the apoptosis regulating function of the wild type fragments [ |
| 6207 | JUP | junction plakoglobin | catenin | 1.0 | furthermore a complex of presenilin and _amp_#x3b2; or _amp_#x3b4; catenin can activate _amp_#x3b3; secretase the enzyme that releases the amyloid fragment a_amp_#x3b2; 1 42 with a consequent increase in the excreted amyloid _amp_#x3b2;. |
| 613 | APOE | apolipoprotein E | apolipoprotein e | 1.0 | apolipoprotein e apoe protects neurons from hydrogen peroxide toxicity and binds specific metal ions including iron which could otherwise catalyze the generation of hydroxyl radicals. |
| 613 | APOE | apolipoprotein E | apolipoprotein e | 1.0 | the gene product of apolipoprotein e allele epsilon 4 has decreased anti oxidant activity compared to alleles epsilon 2 and 3 [ 18 ]. |
| 613 | APOE | apolipoprotein E | apolipoprotein e | 1.0 | apolipoprotein e may also protect from _amp_#x3b2; amyloid peptide toxicity by binding to amyloid _amp_#x3b2; and under certain circumstances acting as kinetic inhibitor of amyloid formation [ 18 ]. |
| 4983 | HMGB1 | high-mobility group box 1 | amphoterin | 1.0 | this receptor can also be engaged by amphoterin and is physiologically involved in neurite outgrowth. |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | superoxide dismutase | 1.0 | some cases of familial amyotrophic lateral sclerosis are characterized by mutations of copper_amp_#x2013;zinc superoxide dismutase. |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | superoxide dismutase | 1.0 | this question arises particularly in view of the observation that superoxide dismutase activities in erythrocytes from patients may be reduced by 50% compared with healthy controls [ 27 ]. |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | superoxide dismutase | 1.0 | superoxide dismutase may act as a peroxidase [ 33 and 34 ] with mutated superoxide dismutase catalyzing substrate oxidation by hydrogen peroxide at a higher rate than wild type enzyme [ 35 ]. |
| 1516 | CAT | catalase | catalase | 1.0 | peroxidase and catalase activities are reduced in the substantia nigra caudate and putamen in parkinson's disease [ 43 ]. |
| 4553 | GPX1 | glutathione peroxidase 1 | cellular glutathione peroxidase | 1.0 | furthermore around 10% of cellular glutathione peroxidase are mitochondrial and there prevent oxidative damage by hydrogen peroxide. |
| 4250 | GGT1 | gamma-glutamyltransferase 1 | glutamyl transpeptidase | 1.0 | of the glutathione cycle is particularly important in the central nervous system because deficiency of enzymes associated with it glutathione synthetase _amp_#x3b3; glutamyl synthetase or _amp_#x3b3; glutamyl transpeptidase leads to defective brain function [ 49 and 50 ] in addition to acidosis and a tendency to hemolysis. |
| 4624 | GSS | glutathione synthetase | glutathione synthetase | 1.0 | the regulatory role of the glutathione cycle is particularly important in the central nervous system because deficiency of enzymes associated with it glutathione synthetase _amp_#x3b3; glutamyl synthetase or _amp_#x3b3; glutamyl transpeptidase leads to defective brain function [ 49 and 50 ] in addition to acidosis and a tendency to hemolysis. |
| 15917 | PLCB1 | phospholipase C, beta 1 (phosphoinositide-specific) | phospholipase c | 1.0 | pla 2 : phopholipase a 2 plc: phospholipase c dag: diacyl glycerol aa: arachidonic acid pkc: protein kinase c gpx: glutathione peroxidase nos: no synthetase ltp: long term potentiation. |
| 9393 | PRKCA | protein kinase C, alpha | protein kinase c | 1.0 | pla 2 : phopholipase a 2 plc: phospholipase c dag: diacyl glycerol aa: arachidonic acid pkc: protein kinase c gpx: glutathione peroxidase nos: no synthetase ltp: long term potentiation. |
| 9393 | PRKCA | protein kinase C, alpha | protein kinase c | 1.0 | maintenance dashed arrows of long term potentiation is mediated by protein kinase c which can be activated by calcium arachidonate or hydroxyl radical from the pathway to induction. |
| 4250 | GGT1 | gamma-glutamyltransferase 1 | glutamyl transpeptidase | 1.0 | glutathione is then transported and converted by membrane bound _amp_#x3b3; glutamyl transpeptidase followed by cleavage by membrane bound dipeptidase. _amp_#x3b3; glutamyl amino acids are transported into the cell and converted to glutamate via oxoproline. |