Document Information

PMID 12684448  (  )
Title Disruption of glial glutamate transport by reactive oxygen species produced in motor neurons.
Abstract Observations of elevated CSF glutamate in amyotrophic lateral sclerosis (ALS), together with findings that motor neurons are selectively vulnerable to glutamate receptor-mediated ("excitotoxic") injury, support an excitotoxic contribution to the motor neuron loss in the disease. However, the basis of the apparent loss of astrocytic glutamate transport capacity in affected areas of motor cortex and spinal cord, which probably underlies the extracellular glutamate elevations, is unexplained. Here, we find that glutamate induces far greater reactive oxygen species (ROS) generation in cultured motor neurons than in other spinal neurons. In addition, we found that the ROS seem to be able to leave the motor neurons and induce oxidation and disruption of glutamate uptake in neighboring astrocytes. Correspondingly, in a transgenic mouse model of ALS, protein oxidation was increased in regions immediately surrounding motor neurons. These results provide a mechanism that can account for the localized loss of glial glutamate transport seen in the disease. Furthermore, the observations lend support for a feedforward model involving reciprocal interactions between motor neurons and glia, which may prove useful in understanding ALS pathogenesis. Irvine, 92697-4292, USA. Neuroscience

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Targets by SciMiner Summary

HUGO ID Symbol Target Name #Occur ActualStr
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))23superoxide dismutase 1 | SOD1 | SOD |
10940SLC1A2solute carrier family 1 (glial high affinity glutamate transporter), member 26GLT-1 | EAAT2 | glt 1 |
4571GRIA1glutamate receptor, ionotropic, AMPA 14glutamate receptor |
4235GFAPglial fibrillary acidic protein3glial fibrillary acidic protein | GFAP |
1516CATcatalase3catalase |

 

Targets by SciMiner Full list

HUGO ID Symbol Name ActualStr Score FlankingText
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD2.2sclerosis ROS glutamate excitotoxicity glutamate transport cell culture free radicals SOD nitrotyrosine AMPA
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD12.2linked to mutations in the enzyme superoxide dismutase 1 (SOD1) SOD1 (Rosen Rosen et al. 1993 the vast majority (90-95%) 90-95%
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD12.2For spinal cord immunohistochemical studies SOD1 G93A transgenic mice (The The Jackson Laboratory Bar Harbor ME
4235GFAPglial fibrillary acidic proteinGFAP2.5studies using the astrocyte-specific marker glial fibrillary acidic protein (GFAP) GFAP confirmed the identity of cells with these morphological characteristics (see
4235GFAPglial fibrillary acidic proteinGFAP2.5blocked and exposed to primary antibody SMI-32 1 5000 and GFAP 1 400 (Dako, Dako Glostrup Denmark glutamate transporter GLT-1 (also
10940SLC1A2solute carrier family 1 (glial high affinity glutamate transporter), member 2GLT-12.5and GFAP 1 400 (Dako, Dako Glostrup Denmark glutamate transporter GLT-1 (also also known as EAAT2 0.17 microg/ml microg ml (kindly
10940SLC1A2solute carrier family 1 (glial high affinity glutamate transporter), member 2EAAT22.5Dako Glostrup Denmark glutamate transporter GLT-1 (also also known as EAAT2 0.17 microg/ml microg ml (kindly kindly supplied by Jeff Rothstein
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD12.2For SOD1 G93A transgenic mouse studies spinal cords were removed from 90-
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD2.2(MK-801)] MK-801 alone or in the presence of antioxidants (SOD, SOD 100 U/ml; U ml catalase 400 U/ml), U ml followed
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD2.2seen in an annular pattern immediately surrounding MNs in the SOD mouse model of ALS is novel and lends support to
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD2.2observed block of this oxidation by an extracellular antioxidant (SOD) SOD provides strong support for the idea that the ROS passes
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD2.2In studies of glutamate transporters in ALS and SOD mutant mouse models there has been discussion as to whether
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD2.2motor neurons and ventral horn in ALS and/or and or SOD mutant mouse models (Abe Abe et al. 1995 Beal et
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD2.2increased nitrotyrosine staining in an annular pattern around MNs in SOD mutant mice suggest that this species may be involved
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD12.2a critical involvement of both cell types in the mutant SOD1 mouse models of ALS development of disease seems to require
10940SLC1A2solute carrier family 1 (glial high affinity glutamate transporter), member 2GLT-12.5an explanation for previous reports of oxidative modifications of the GLT-1 transporter in ALS (Pedersen Pedersen et al. 1998 Trotti et
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD2.2compatible with a multiplicity of inciting mechanisms (e.g., e.g. mutant SOD leading into a common self-propagating disease pathway
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD2.2MK-801 alone ( left or with addition of the antioxidant SOD (100 100 U/ml) U ml to the bath (+ AO
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD2.2both the absence ( black or presence ( white of SOD with minimal response in other neurons ( squares
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD2.2( bottom left or presence ( bottom right of extracellular SOD (+ AO
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD2.2micro M MK-801 alone or with addition of the antioxidants SOD (100 100 U/ml) U ml and catalase (400 400 U/ml)
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD12.2Lumbar spinal cord sections from 3-month-old SOD1 transgenic mice ( G93A and nontransgenic controls ( non-TG (
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD2.2With the addition of a cell-impermeant antioxidant enzyme (SOD, SOD 100 U/ml), U ml despite closely matched MN Delta F
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD2.2This selective effect of extracellular SOD on astrocytic responses suggests strongly that the ROS generated in
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD2.2extracellular bath (in in which it can be quenched by SOD before inducing oxidation in neighboring glia
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD2.2uptake was prevented by addition of cell-impermeant antioxidant enzymes (SOD, SOD 100 U/ml; U ml catalase 400 U/ml) U ml to
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD12.2use of transgenic mice expressing the G93A mutant form of SOD1 associated with familial forms of ALS (Gurney Gurney et al.
4571GRIA1glutamate receptor, ionotropic, AMPA 1glutamate receptor1.0observations of elevated csf glutamate in amyotrophic lateral sclerosis als together with findings that motor neurons are selectively vulnerable to glutamate receptor mediated "excitotoxic" injury support an excitotoxic contribution to the motor neuron loss in the disease.
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))superoxide dismutase 11.0although a small percentage 1 2% of cases have been linked to mutations in the enzyme superoxide dismutase 1 sod1 rosen et al. 1993 the vast majority 90 95% are sporadic.
4571GRIA1glutamate receptor, ionotropic, AMPA 1glutamate receptor1.0mns seem to possess large numbers of unusual ampa type glutamate receptor channels that are directly permeable to ca carriedo et al. 1995 1996 ; williams et al. 1997 ; vandenberghe et al. 2000 and activation of these channels with the selective agonists ampa or kainate ind
4235GFAPglial fibrillary acidic proteinglial fibrillary acidic protein1.0control studies using the astrocyte specific marker glial fibrillary acidic protein gfap confirmed the identity of cells with these morphological characteristics see fig 1 b .
10940SLC1A2solute carrier family 1 (glial high affinity glutamate transporter), member 2glt 11.0cultures were fixed in 4% paraformaldehyde blocked and exposed to primary antibody [smi 32 1:5000 and gfap 1:400 dako glostrup denmark ; glutamate transporter glt 1 also known as eaat2 0.17 microg/ml kindly supplied by jeff rothstein johns hopkins university baltimore md ; 3 nitrotyrosine 10 microg/ml upstate biotechnology waltham ma ].
1516CATcatalasecatalase1.0xposed for 15 min to sham wash or to kainate [100 micro m plus + 5 methyl 10 11 dihydro 5h dibenzo [a d] cyclohepten 5 10 imine maleate mk 801 ] alone or in the presence of antioxidants sod 100 u/ml; catalase 400 u/ml followed after another 10 min by incubation in [ h]glutamate 2 microci/ml in hss for 5 min.
4571GRIA1glutamate receptor, ionotropic, AMPA 1glutamate receptor1.0behave similarly to those in situ with both seeming to possess large numbers of ca permeable ampa channels to show poor intracellular ca buffering and to be selectively vulnerable to injury caused by glutamate receptor activation o'brien and fischbach 1986 ; hugon et al. 1989 ; rothstein et al. 1993 ; carriedo et al. 1996 2000 ; williams et al. 1997 ; vandenberghe et al. 1998 ; palecek et al. 1999 .
4571GRIA1glutamate receptor, ionotropic, AMPA 1glutamate receptor1.0thus the relatively selective ros generation we observe in cultured mns in response to glutamate receptor activation and the ability of this ros to escape the cell and affect the surrounding microenvironment is likely to model events that can occur in vivo .
10940SLC1A2solute carrier family 1 (glial high affinity glutamate transporter), member 2glt 11.0in addition the suggestion that the ros can exit mns and affect surrounding astrocytes provides an explanation for previous reports of oxidative modifications of the glt 1 transporter in als pedersen et al. 1998 ; trotti et al. 1999 ; deitch et al. 2002 .
10940SLC1A2solute carrier family 1 (glial high affinity glutamate transporter), member 2glt 11.0c under confocal microscopy the close spatial relationship between the mn smi 32 red and glial glutamate transporters anti glt 1 green is apparent.
1516CATcatalasecatalase1.0a spinal cultures were exposed to sham wash or to kainate ka ; 100 micro m plus 10 micro m mk 801 alone or with addition of the antioxidants sod 100 u/ml and catalase 400 u/ml to the bath ka+ao before [ h]glutamate uptake assays as described.
1516CATcatalasecatalase1.0furthermore this local decrease in uptake was prevented by addition of cell impermeant antioxidant enzymes sod 100 u/ml; catalase 400 u/ml to the bath.