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PMID	16877542 ( )
Title	The inflammatory NADPH oxidase enzyme modulates motor neuron degeneration in amyotrophic lateral sclerosis mice.
Abstract	ALS is a fatal paralytic disorder characterized by a progressive loss of spinal cord motor neurons. Herein, we show that NADPH oxidase, the main reactive oxygen species-producing enzyme during inflammation, is activated in spinal cords of ALS patients and in spinal cords in a genetic animal model of this disease. We demonstrate that inactivation of NADPH oxidase in ALS mice delays neurodegeneration and extends survival. We also show that NADPH oxidase-derived oxidant products damage proteins such as insulin-like growth factor 1 (IGF1) receptors, which are located on motor neurons. Our in vivo and in vitro data indicate that such an oxidative modification hinders the IGF1/Akt survival pathway in motor neurons. These findings suggest a non-cell-autonomous mechanism through which inflammation could hasten motor neuron death and contribute to the selective motor neuronal degeneration in ALS. America

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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))	109	superoxide dismutase 1 \| SOD1 \| ALS \| SOD \|
5464	IGF1	insulin-like growth factor 1 (somatomedin C)	50	insulin like growth factor 1 \| IGF1-treated \| IGF1-mediated \|
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	41	nadph oxidase \|
2578	CYBB	cytochrome b-245, beta polypeptide (chronic granulomatous disease)	33	gp91 phox \|
391	AKT1	v-akt murine thymoma viral oncogene homolog 1	18	Akt \|
7661	NCF2	neutrophil cytosolic factor 2 (65kDa, chronic granulomatous disease, autosomal 2)	1	p67 phox \|
1693	CD68	CD68 molecule	1	CD68 \|
7577	MYH7	myosin, heavy chain 7, cardiac muscle, beta	1	myosin heavy chain \|
936	BAD	BCL2-antagonist of cell death	1	BAD \|
23212	MYH14	myosin, heavy chain 14	1	myosin \|
4235	GFAP	glial fibrillary acidic protein	1	glial fibrillary acidic protein \|
1516	CAT	catalase	1	catalase \|
4141	GAPDH	glyceraldehyde-3-phosphate dehydrogenase	1	GAPDH \|

Targets by SciMiner Full list

HUGO ID	Symbol	Name	ActualStr	Score	FlankingText
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	ALS	2.2	Abstract ALS is a fatal paralytic disorder characterized by a progressive loss
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	ALS	2.2	species-producing enzyme during inflammation is activated in spinal cords of ALS patients and in spinal cords in a genetic animal model
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	ALS	2.2	We demonstrate that inactivation of NADPH oxidase in ALS mice delays neurodegeneration and extends survival
5464	IGF1	insulin-like growth factor 1 (somatomedin C)	IGF1	2.0	products damage proteins such as insulin-like growth factor 1 (IGF1) IGF1 receptors which are located on motor neurons
5464	IGF1	insulin-like growth factor 1 (somatomedin C)	IGF1	2.0	data indicate that such an oxidative modification hinders the IGF1/Akt IGF1 Akt survival pathway in motor neurons
391	AKT1	v-akt murine thymoma viral oncogene homolog 1	Akt	0.3	indicate that such an oxidative modification hinders the IGF1/Akt IGF1 Akt survival pathway in motor neurons
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	ALS	2.2	death and contribute to the selective motor neuronal degeneration in ALS
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	ALS	2.2	Keywords Akt ALS microglia oxidation non-cell autonomous
391	AKT1	v-akt murine thymoma viral oncogene homolog 1	Akt	0.2	Keywords Akt ALS microglia oxidation non-cell autonomous
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD1	2.2	Transgenic SOD1 G93A mice [C57BL/6J-TgN(SOD1-G93A)1Gur C57BL 6J-TgN SOD1-G93A 1Gur dl were crossed
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD1	2.2	for details about the timeline of behavioral abnormalities in transgenic SOD1 G93A mice
4141	GAPDH	glyceraldehyde-3-phosphate dehydrogenase	GAPDH	0.0	phox glial fibrillary acidic protein macrophage antigen complex 1 and GAPDH and PCR conditions are presented in Supporting Text
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	ALS	2.2	60.5 _amp_#x000b1 10.2 years and 8.0 _amp_#x000b1 2.6 h respectively ALS group ( n = 6 60.5 _amp_#x000b1 4.2 years and
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	ALS	2.2	For the ALS patients the mean duration of disease was 19.3 _amp_#x000b1 2.6
5464	IGF1	insulin-like growth factor 1 (somatomedin C)	IGF1	2.0	Phosphorylation of Akt and cell viability in response to IGF1 recombinant and to H 2 O 2 or activated BV2
391	AKT1	v-akt murine thymoma viral oncogene homolog 1	Akt	0.0	Phosphorylation of Akt and cell viability in response to IGF1 recombinant and to
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	ALS	2.2	NADPH Oxidase Is Up-Regulated in Inflamed Spinal Cords of ALS Mice
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD1	2.2	stages of the disease in transgenic mice expressing mutant human SOD1 with a substitution of glycine to alanine in position 93
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD1	2.2	a substitution of glycine to alanine in position 93 (SOD1 SOD1 G93A the most widely studied model of ALS
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	ALS	2.2	93 (SOD1 SOD1 G93A the most widely studied model of ALS
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	ALS	2.2	cord which carries the brunt of the pathology in this ALS model was determined by analyzing its catalytic subunit gp91 phox
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD1	2.2	whole-tissue extracts of spinal cord rose over time in transgenic SOD1 G93A mice ( Fig 1 A B D and E
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD1	2.2	in membrane fractions of spinal cord extracts from symptomatic transgenic SOD1 G93A mice ( Fig 1 C indicating that this cytosolic
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD1	2.2	Histological evaluation of the spinal cord of symptomatic transgenic SOD1 G93A mice showed numerous gp91 phox -positive cells primarily in
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD1	2.2	NADPH Oxidase Causes Protein Oxidation in Transgenic SOD1 G93A Mice
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD1	2.2	characterized the status of spinal cord NADPH oxidase in transgenic SOD1 G93A mice by probing for formation of ROS and evidence
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD1	2.2	In contrast in symptomatic transgenic SOD1 G93A mice carrying the wild-type gp91 phox allele (SOD SOD
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD	2.2	SOD1 G93A mice carrying the wild-type gp91 phox allele (SOD SOD G93A /gp91 gp91 phox spinal cord ethidium fluorescence was intense
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD1	2.2	In symptomatic transgenic SOD1 G93A mice carrying the nonfunctional mutant allele (SOD SOD G93A
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD	2.2	transgenic SOD1 G93A mice carrying the nonfunctional mutant allele (SOD SOD G93A /gp91 gp91 phox_amp_#x02212 ( 12 spinal cord ethidium fluorescence
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD1	2.2	Symptomatic transgenic SOD1 G93A /gp91 gp91 phox mice but not age-matched SOD1 G93A
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD1	2.2	transgenic SOD1 G93A /gp91 gp91 phox mice but not age-matched SOD1 G93A /gp91 gp91 phox_amp_#x02212 mice had increased levels of spinal
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD1	2.2	for protein carbonyl adducts occurred in spinal cord sections from SOD1 G93A /gp91 gp91 phox mice at the level of cells
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	ALS	2.2	NADPH Oxidase Induction and Neuronal Protein Carbonylation in Sporadic ALS
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD1	2.2	to determine whether the NADPH oxidase alterations identified in transgenic SOD1 G93A mice were also present in human sporadic ALS the
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	ALS	2.2	transgenic SOD1 G93A mice were also present in human sporadic ALS the most common form of the disease ( 1
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	ALS	2.2	was _amp_#x02248 3-fold higher and its immunoreactivity robust in sporadic ALS spinal cords ( Fig 2 E
1693	CD68	CD68 molecule	CD68	0.3	latter gp91 phox -positive cells colocalized with the microglial-associated antigen CD68 ( Fig 2 F and were identified in all of
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	ALS	2.2	2 F and were identified in all of the typical ALS loci of neurodegeneration including the anterior horn and the lateral
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	ALS	2.2	protein carbonyl adducts in postmortem spinal cord sections from sporadic ALS cases which seemed to be mainly associated with large motor
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	ALS	2.2	for protein carbonyl adducts per lumbar spinal cord section in ALS patients whereas no such immunoreactive motor neurons were seen in
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD1	2.2	Deletion of gp91 phox Mitigates the Disease Phenotype in Transgenic SOD1 G93A Mice
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD1	2.2	of NADPH oxidase activation on the disease phenotype in the SOD1 G93A mouse model of ALS
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	ALS	2.2	the disease phenotype in the SOD1 G93A mouse model of ALS
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD1	2.2	Transgenic SOD1 G93A /gp91 gp91 phox_amp_#x02212 mice reached end-stage paralysis (defined defined
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD1	2.2	a loss of the righting reflex later than their transgenic SOD1 G93A /gp91 gp91 phox counterparts ( Fig 3 A which
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD1	2.2	3 A which resulted in a longer lifespan of transgenic SOD1 G93A /gp91 gp91 phox_amp_#x02212 mice (log-rank log-rank test = 15.3
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD1	2.2	Compared with end-stage transgenic SOD1 G93A /gp91 gp91 phox mice age-matched transgenic SOD1 G93A /gp91
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD1	2.2	end-stage transgenic SOD1 G93A /gp91 gp91 phox mice age-matched transgenic SOD1 G93A /gp91 gp91 phox_amp_#x02212 mice had _amp_#x02248 50% more anterior
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD1	2.2	the glial cytokine IL-1_amp_#x003b2 did not differ between age-matched transgenic SOD1 G93A /gp91 gp91 phox mice and SOD1 G93A /gp91 gp91
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD1	2.2	between age-matched transgenic SOD1 G93A /gp91 gp91 phox mice and SOD1 G93A /gp91 gp91 phox_amp_#x02212 mice (Fig Fig 7 which is
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD1	2.2	the deficit of gp91 phox were the levels of human SOD1 in transgenic SOD1 G93A mice (Fig Fig 7 or the
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD1	2.2	gp91 phox were the levels of human SOD1 in transgenic SOD1 G93A mice (Fig Fig 7 or the size of muscle
23212	MYH14	myosin, heavy chain 14	myosin	2.2	are mainly composed of fast-twitch fibers and by immunostaining for myosin heavy chain we did not observe any obvious alteration in
5464	IGF1	insulin-like growth factor 1 (somatomedin C)	IGF1	2.0	NADPH Oxidase Impairs the Insulin-Like Growth Factor 1 (IGF1)/Akt IGF1 Akt Pathway in Transgenic SOD1 G93A Mice
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD1	2.2	Insulin-Like Growth Factor 1 (IGF1)/Akt IGF1 Akt Pathway in Transgenic SOD1 G93A Mice
391	AKT1	v-akt murine thymoma viral oncogene homolog 1	Akt	0.3	NADPH Oxidase Impairs the Insulin-Like Growth Factor 1 (IGF1)/Akt IGF1 Akt Pathway in Transgenic SOD1 G93A Mice
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	ALS	2.2	explored whether NADPH oxidase-mediated protein modifications might promote neurodegeneration in ALS by damaging essential surviving pathways for motor neurons such as
5464	IGF1	insulin-like growth factor 1 (somatomedin C)	IGF1	2.0	by damaging essential surviving pathways for motor neurons such as IGF1
5464	IGF1	insulin-like growth factor 1 (somatomedin C)	IGF1	2.0	After IGF1 was immunoprecipitated from spinal cord extracts it was probed for
5464	IGF1	insulin-like growth factor 1 (somatomedin C)	IGF1	2.0	This approach failed to reveal evidence of IGF1 oxidation in any of the studied mouse genotypes (data data
5464	IGF1	insulin-like growth factor 1 (somatomedin C)	IGF1	2.0	carbonyl adducts were evident in the _amp_#x003b1 -chain of the IGF1 tyrosine kinase cognate receptor in the spinal cord of symptomatic
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD1	2.2	kinase cognate receptor in the spinal cord of symptomatic transgenic SOD1 G93A /gp91 gp91 phox mice ( Fig 4 A and
5464	IGF1	insulin-like growth factor 1 (somatomedin C)	IGF1	2.0	B similar results were obtained for the _amp_#x003b2 -chain of IGF1 receptor (data data not shown
5464	IGF1	insulin-like growth factor 1 (somatomedin C)	IGF1	2.0	This finding might be quite significant because IGF1 receptors in mouse spinal cords were detected almost exclusively on
5464	IGF1	insulin-like growth factor 1 (somatomedin C)	IGF1	2.0	Contrasting with the IGF1 receptor findings oxidation indices in the intracellular serine/threonine serine threonine
5464	IGF1	insulin-like growth factor 1 (somatomedin C)	IGF1	2.0	in the intracellular serine/threonine serine threonine kinase Akt which transduces IGF1 receptor signaling ( 15 did not differ between symptomatic transgenic
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD1	2.2	receptor signaling ( 15 did not differ between symptomatic transgenic SOD1 G93A mice and their nontransgenic littermates
391	AKT1	v-akt murine thymoma viral oncogene homolog 1	Akt	0.0	findings oxidation indices in the intracellular serine/threonine serine threonine kinase Akt which transduces IGF1 receptor signaling ( 15 did not differ
5464	IGF1	insulin-like growth factor 1 (somatomedin C)	IGF1	2.0	These results suggest that the entire IGF1 molecular pathway is not oxidatively modified by inflammation in this
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	ALS	2.2	molecular pathway is not oxidatively modified by inflammation in this ALS model
5464	IGF1	insulin-like growth factor 1 (somatomedin C)	IGF1	2.0	Next we compared selected IGF1 transduction events among the different mouse groups
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD1	2.2	Although mutant SOD1 is expressed in all cells markers of IGF1 transduction such
5464	IGF1	insulin-like growth factor 1 (somatomedin C)	IGF1	2.0	Although mutant SOD1 is expressed in all cells markers of IGF1 transduction such as phospho-IGF1 receptor phospho-Akt (data data not shown
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD1	2.2	smaller glia-like cells in spinal cord sections of symptomatic transgenic SOD1 G93A mice
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD1	2.2	phospho-IGF1 receptor-immunoreactive cells in spinal cord sections from symptomatic transgenic SOD1 G93A /gp91 gp91 phox mice than from age-matched SOD1 G93A
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD1	2.2	transgenic SOD1 G93A /gp91 gp91 phox mice than from age-matched SOD1 G93A /gp91 gp91 phox_amp_#x02212 mice ( Fig 4 C _amp_#x02013
936	BAD	BCL2-antagonist of cell death	BAD	0.3	( Fig 4 H _amp_#x02013 J and smaller phospho-BAD total BAD ratios ( Fig 4 K and L in symptomatic transgenic
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD1	2.2	ratios ( Fig 4 K and L in symptomatic transgenic SOD1 G93A /gp91 gp91 phox mice compared with their age-matched SOD1
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD1	2.2	SOD1 G93A /gp91 gp91 phox mice compared with their age-matched SOD1 G93A /gp91 gp91 phox_amp_#x02212 counterparts
391	AKT1	v-akt murine thymoma viral oncogene homolog 1	Akt	0.0	There were also smaller phospho-Akt total Akt ratios ( Fig 4 F and G as well as
391	AKT1	v-akt murine thymoma viral oncogene homolog 1	Akt	0.0	fewer cells that were immunoreactive for a downstream target of Akt phospho-BAD ( Fig 4 H _amp_#x02013 J and smaller phospho-BAD
5464	IGF1	insulin-like growth factor 1 (somatomedin C)	IGF1	2.0	These data further support the idea that oxidative modification of IGF1 receptor in symptomatic transgenic SOD1 G93A /gp91 gp91 phox mice
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD1	2.2	idea that oxidative modification of IGF1 receptor in symptomatic transgenic SOD1 G93A /gp91 gp91 phox mice is associated with a range
5464	IGF1	insulin-like growth factor 1 (somatomedin C)	IGF1	2.0	Microglial-Derived ROS Recapitulate the IGF1/Akt IGF1 Akt Pathway Defect in Vitro
391	AKT1	v-akt murine thymoma viral oncogene homolog 1	Akt	0.3	Microglial-Derived ROS Recapitulate the IGF1/Akt IGF1 Akt Pathway Defect in Vitro
5464	IGF1	insulin-like growth factor 1 (somatomedin C)	IGF1	2.0	To test the idea that NADPH oxidase-derived ROS could impair IGF1 pathway function an in vitro cell system using the neuron-like
5464	IGF1	insulin-like growth factor 1 (somatomedin C)	IGF1	2.0	were briefly incubated with 0.1_amp_#x02013 100 _amp_#x003bc M human recombinant IGF1 in the presence of overnight-preconditioned serum-free medium supplemented with or
5464	IGF1	insulin-like growth factor 1 (somatomedin C)	IGF1	2.0	to provide a constant flux of H 2 O 2 IGF1 pathway responsiveness was monitored by Akt phosphorylation
391	AKT1	v-akt murine thymoma viral oncogene homolog 1	Akt	0.0	H 2 O 2 IGF1 pathway responsiveness was monitored by Akt phosphorylation
5464	IGF1	insulin-like growth factor 1 (somatomedin C)	IGF1	2.0	Exposure to IGF1 caused a dose-dependent phosphorylation of Akt in SH-SY5Y cells (
391	AKT1	v-akt murine thymoma viral oncogene homolog 1	Akt	0.0	Exposure to IGF1 caused a dose-dependent phosphorylation of Akt in SH-SY5Y cells ( Fig 5 A and B and
5464	IGF1	insulin-like growth factor 1 (somatomedin C)	IGF1	2.0	Conversely IGF1 barely increased Akt phosphorylation in the neuroblastoma cell lines that
391	AKT1	v-akt murine thymoma viral oncogene homolog 1	Akt	0.0	Conversely IGF1 barely increased Akt phosphorylation in the neuroblastoma cell lines that were exposed to
5464	IGF1	insulin-like growth factor 1 (somatomedin C)	IGF1-mediated	1.5	of H 2 O 2 ( Fig 5 E attenuated IGF1-mediated Akt phosphorylation in the neuroblastoma cell line ( Fig 5
391	AKT1	v-akt murine thymoma viral oncogene homolog 1	Akt	0.2	H 2 O 2 ( Fig 5 E attenuated IGF1-mediated Akt phosphorylation in the neuroblastoma cell line ( Fig 5 C
5464	IGF1	insulin-like growth factor 1 (somatomedin C)	IGF1	2.0	to LPS-activated microglial-conditioned medium the Akt phosphorylation response to the IGF1 recombinant remained depressed and at 72 h a reduction of
5464	IGF1	insulin-like growth factor 1 (somatomedin C)	IGF1	2.0	a reduction of cell viability indistinguishable from the condition without IGF1 was observed ( Fig 5 F
391	AKT1	v-akt murine thymoma viral oncogene homolog 1	Akt	0.0	Upon longer exposure to LPS-activated microglial-conditioned medium the Akt phosphorylation response to the IGF1 recombinant remained depressed and at
5464	IGF1	insulin-like growth factor 1 (somatomedin C)	IGF1-mediated	1.5	However both the alteration of IGF1-mediated Akt phosphorylation and the loss of cell viability mediated by
391	AKT1	v-akt murine thymoma viral oncogene homolog 1	Akt	0.2	However both the alteration of IGF1-mediated Akt phosphorylation and the loss of cell viability mediated by LPS-activated
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	ALS	2.2	Experimental evidence supports a model for ALS neurodegeneration in which nonneuronal cells such as microglia contribute to
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD1	2.2	Conversely in transgenic SOD1 G93A mice paralleling the worsening of the ALS phenotype there
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	ALS	2.2	in transgenic SOD1 G93A mice paralleling the worsening of the ALS phenotype there was an intensification of spinal cord microgliosis accompanied
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	ALS	2.2	of oxidatively damaging nearby macromolecules and cells homed within inflamed ALS tissues
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD1	2.2	were markedly elevated in spinal cord extracts of symptomatic transgenic SOD1 G93A mice for the most part in a NADPH oxidase-dependent
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	ALS	2.2	was also found in postmortem spinal cords from human sporadic ALS cases ( Fig 2 supporting the conclusion that the occurrence
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	ALS	2.2	occurrence of inflammation-mediated oxidative damage is not restricted to familial ALS caused by SOD1 mutations but is also a pathological hallmark
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD1	2.2	oxidative damage is not restricted to familial ALS caused by SOD1 mutations but is also a pathological hallmark of the prevalent
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	ALS	2.2	a pathological hallmark of the prevalent nonfamilial sporadic form of ALS
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD1	2.2	of the gp91 phox subunit of NADPH oxidase in transgenic SOD1 G93A mice eliminates the production of microglial-derived ROS ( Fig
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	ALS	2.2	M and importantly prolongs survival and retards neurodegeneration in this ALS model ( Fig 3
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD1	2.2	Deletion of gp91 phox in transgenic SOD1 G93A mice did not alter the spinal cord microglial response
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD1	2.2	the spinal cord microglial response or the expression of human SOD1 in transgenic SOD1 G93A mice (Fig Fig 7 which is
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD1	2.2	microglial response or the expression of human SOD1 in transgenic SOD1 G93A mice (Fig Fig 7 which is a known determinant
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	ALS	2.2	which is a known determinant of disease severity in this ALS model ( 18
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD1	2.2	Consequently the attenuated phenotype seen in transgenic SOD1 G93A /gp91 gp91 phox_amp_#x02212 mice is attributable to the lack
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD1	2.2	either an impaired microglial response or expression of the human SOD1 G93A transgene
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	ALS	2.2	NADPH oxidase contributes to the degeneration of motor neurons in ALS
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	ALS	2.2	in the pathogenesis of chronic noninfectious pathological conditions such as ALS
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD1	2.2	magnitude of benefit afforded by gp91 phox deletion in transgenic SOD1 G93A mice argues that targeting neuroinflammation by inhibiting just one
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	ALS	2.2	not be sufficient to produce robust and lasting neuroprotection in ALS patients
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	ALS	2.2	However the chronic nature of ALS suggests that neuroinflammation is likely protracted and not as strong
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	ALS	2.2	oxidative stress with the selective demise of motor neurons in ALS
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	ALS	2.2	of those already compromised as motor neurons probably are in ALS
5464	IGF1	insulin-like growth factor 1 (somatomedin C)	IGF1	2.0	Relevant to the latter scenario are our results for IGF1 a trophic factor that is known to promote motor neuron
5464	IGF1	insulin-like growth factor 1 (somatomedin C)	IGF1	2.0	In this study we indeed found that receptors for IGF1 were primarily expressed on motor neurons in mouse spinal cords
5464	IGF1	insulin-like growth factor 1 (somatomedin C)	IGF1	2.0	in mouse spinal cords (Fig Fig 8 and that the IGF1 signaling pathway was impaired by a NADPH oxidase-dependent mechanism in
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD1	2.2	was impaired by a NADPH oxidase-dependent mechanism in symptomatic transgenic SOD1 G93A mice ( Fig 4
5464	IGF1	insulin-like growth factor 1 (somatomedin C)	IGF1	2.0	Although IGF1 per se did not seem to be damaged by inflammation
5464	IGF1	insulin-like growth factor 1 (somatomedin C)	IGF1	2.0	by inflammation NADPH oxidase did stimulate the oxidative modification of IGF1 receptors ( Fig 4
5464	IGF1	insulin-like growth factor 1 (somatomedin C)	IGF1	2.0	The ligand-dependent kinase activation of IGF1 receptor relies on its arrangement into a heterotetrameric 2_amp_#x003b1;/2_amp_#x003b2;-chain 2_amp_#x003b1
5464	IGF1	insulin-like growth factor 1 (somatomedin C)	IGF1	2.0	It may thus be predicted that oxidation of the IGF1 receptor main extracellular domains (i.e., i.e. the _amp_#x003b1 -chains could
5464	IGF1	insulin-like growth factor 1 (somatomedin C)	IGF1	2.0	molecular events that are normally elicited by ligation of the IGF1 receptor including autophosphorylation and Akt phosphorylation were indeed abated by
391	AKT1	v-akt murine thymoma viral oncogene homolog 1	Akt	0.0	elicited by ligation of the IGF1 receptor including autophosphorylation and Akt phosphorylation were indeed abated by ROS in a microglial NADPH
5464	IGF1	insulin-like growth factor 1 (somatomedin C)	IGF1	2.0	data also show that microglial NADPH oxidase by impairing the IGF1 signaling pathway renders SH-SY5Y cells in our in vitro system
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD1	2.2	to withstand the toxicity of etiologic agents such as mutant SOD1
5464	IGF1	insulin-like growth factor 1 (somatomedin C)	IGF1	2.0	Muscle-specific expression of IGF1 stabilizes neuromuscular junctions reduces inflammation in the spinal cord and
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD1	2.2	the spinal cord and enhances motor neuronal survival in transgenic SOD1 G93A mice ( 23
5464	IGF1	insulin-like growth factor 1 (somatomedin C)	IGF1	2.0	did not find any evidence that the rescue of the IGF1 pathway by abrogating NADPH oxidase was associated with muscle hypertrophy
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD1	2.2	Nevertheless whether transgenic SOD1 G93A mice carrying the gp91 phox null mutation reach end-stage
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD1	2.2	Injection of transgenic SOD1 G93A mice with an adeno-associated virus carrying an IGF1 gene
5464	IGF1	insulin-like growth factor 1 (somatomedin C)	IGF1	2.0	transgenic SOD1 G93A mice with an adeno-associated virus carrying an IGF1 gene prolongs survival in these animals ( 20 24
5464	IGF1	insulin-like growth factor 1 (somatomedin C)	IGF1	2.0	but instead may blunt the motor neuron survival response to IGF1 in ALS
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	ALS	2.2	may blunt the motor neuron survival response to IGF1 in ALS
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	ALS	2.2	Perhaps the modest change in ALS progression that is seen in patients treated with human recombinant
5464	IGF1	insulin-like growth factor 1 (somatomedin C)	IGF1	2.0	progression that is seen in patients treated with human recombinant IGF1 ( 25 may be related to the issue raised above
5464	IGF1	insulin-like growth factor 1 (somatomedin C)	IGF1	2.0	It may thus be argued that optimal therapeutic response to IGF1 in diseases such as ALS may rely on a concomitant
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	ALS	2.2	that optimal therapeutic response to IGF1 in diseases such as ALS may rely on a concomitant administration of this trophic factor
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD1	2.2	oxidase stimulates carbonylation of spinal cord motor neurons in transgenic SOD1 G93A mice
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD1	2.2	E in 1-month-old (asymptomatic) asymptomatic to 4-month-old (end-stage) end-stage transgenic SOD1 (more more ...
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	ALS	2.2	with motor neuron carbonylation in the spinal cord of sporadic ALS patients
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	ALS	2.2	spinal cord extracts from six normal controls and six age-matched ALS patients
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD1	2.2	of gp91 phox increases lifespan and lessens neurodegeneration in transgenic SOD1 G93A mice
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD1	2.2	( A Survival comparison of transgenic SOD1 G93A /gp91 gp91 phox mice (red) red (122.0 122.0 _amp_#x000b1
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD1	2.2	(122.0 122.0 _amp_#x000b1 1.7 days n = 19 and transgenic SOD1 G93A /gp91 gp91 phox_amp_#x02212 littermates (more more ...
5464	IGF1	insulin-like growth factor 1 (somatomedin C)	IGF1	2.0	Modulation of the IGF1/Akt IGF1 Akt pathway by NADPH oxidase-derived ROS
391	AKT1	v-akt murine thymoma viral oncogene homolog 1	Akt	0.3	Modulation of the IGF1/Akt IGF1 Akt pathway by NADPH oxidase-derived ROS
5464	IGF1	insulin-like growth factor 1 (somatomedin C)	IGF1	2.0	( A Immunoprecipitation of IGF1 receptor _amp_#x003b1 -chain followed by OxyBlot (upper upper blot and
5464	IGF1	insulin-like growth factor 1 (somatomedin C)	IGF1	2.0	by OxyBlot (upper upper blot and immunoblot for spinal cord IGF1 receptor _amp_#x003b1 -chain (lower lower blot
5464	IGF1	insulin-like growth factor 1 (somatomedin C)	IGF1	2.0	Glucose oxidase- and microglial-derived ROS impair the IGF1 Akt pathway in vitro
391	AKT1	v-akt murine thymoma viral oncogene homolog 1	Akt	0.2	Glucose oxidase- and microglial-derived ROS impair the IGF1 Akt pathway in vitro
5464	IGF1	insulin-like growth factor 1 (somatomedin C)	IGF1-treated	1.5	upper blot and total Akt (lower lower blot immunoblots of IGF1-treated SH-SY5Y cells exposed or not exposed to 75 _amp_#x003bc M
391	AKT1	v-akt murine thymoma viral oncogene homolog 1	Akt	0.0	( A Phospho-Akt (upper upper blot and total Akt (lower lower blot immunoblots of IGF1-treated SH-SY5Y cells exposed or
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD1	2.2	ROS reactive oxygen species SOD1 superoxide dismutase 1 IGF1 insulin-like growth factor 1
5464	IGF1	insulin-like growth factor 1 (somatomedin C)	IGF1	2.0	ROS reactive oxygen species SOD1 superoxide dismutase 1 IGF1 insulin-like growth factor 1
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	ALS	2.2	ALS is the most common adult-onset paralytic disease and is characterized
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD1	2.2	dominant mutations in the gene for superoxide dismutase 1 (SOD1) SOD1 cause familial ALS ( 2 3
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	ALS	2.2	the gene for superoxide dismutase 1 (SOD1) SOD1 cause familial ALS ( 2 3
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD1	2.2	Overexpression of SOD1 mutants in rodents emulate clinical and pathological hallmarks of ALS
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	ALS	2.2	SOD1 mutants in rodents emulate clinical and pathological hallmarks of ALS through a toxic gain of function ( 4
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD1	2.2	mixture of neuronal and nonneuronal cells expressing wild-type or mutant SOD1 ( 5 investigation of these animals suggested that nonneuronal cells
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD1	2.2	Corroborating this hypothesis is the demonstration that reduction of mutant SOD1 selectively in microglia extended survival in transgenic SOD1 G37R mice
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD1	2.2	of mutant SOD1 selectively in microglia extended survival in transgenic SOD1 G37R mice ( 6
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	ALS	2.2	we undertook the study of NADPH oxidase in both human ALS and one of its genetic models
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	ALS	2.2	and mouse postmortem tissues indicate that spinal cord microgliosis in ALS is accompanied with an up-regulation of NADPH oxidase
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	herein we show that nadph oxidase the main reactive oxygen species producing enzyme during inflammation is activated in spinal cords of als patients and in spinal cords in a genetic animal model of this disease.
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	we demonstrate that inactivation of nadph oxidase in als mice delays neurodegeneration and extends survival.
5464	IGF1	insulin-like growth factor 1 (somatomedin C)	insulin like growth factor 1	1.0	we also show that nadph oxidase derived oxidant products damage proteins such as insulin like growth factor 1 igf1 receptors which are located on motor neurons.
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	we also show that nadph oxidase derived oxidant products damage proteins such as insulin like growth factor 1 igf1 receptors which are located on motor neurons.
2578	CYBB	cytochrome b-245, beta polypeptide (chronic granulomatous disease)	gp91 phox	1.0	transgenic sod1 g93a mice [c57bl/6j tgn sod1 g93a 1gur dl ] were crossed with gp91 phox deficient mice b6.129s6 cybb tm1din .
2578	CYBB	cytochrome b-245, beta polypeptide (chronic granulomatous disease)	gp91 phox	1.0	primer sequences for gp91 phox glial fibrillary acidic protein macrophage antigen complex 1 and gapdh and pcr conditions are presented in supporting text .
4235	GFAP	glial fibrillary acidic protein	glial fibrillary acidic protein	1.0	primer sequences for gp91 phox glial fibrillary acidic protein macrophage antigen complex 1 and gapdh and pcr conditions are presented in supporting text .
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	nadph oxidase is up regulated in inflamed spinal cords of als mice.
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	to determine the role of nadph oxidase in motor neuron degeneration we first evaluated its expression at different stages of the disease in transgenic mice expressing mutant human sod1 with a substitution of glycine to alanine in position
2578	CYBB	cytochrome b-245, beta polypeptide (chronic granulomatous disease)	gp91 phox	1.0	expression of nadph oxidase in the spinal cord which carries the brunt of the pathology in this als model was determined by analyzing its catalytic subunit gp91 phox .
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	expression of nadph oxidase in the spinal cord which carries the brunt of the pathology in this als model was determined by analyzing its catalytic subunit gp91 phox .
2578	CYBB	cytochrome b-245, beta polypeptide (chronic granulomatous disease)	gp91 phox	1.0	both gp91 phox message and protein contents in whole tissue extracts of spinal cord rose over time in transgenic sod1 g93a mice fig 1 a b d and e in concert with the development of a glial response fig 6 which is p
7661	NCF2	neutrophil cytosolic factor 2 (65kDa, chronic granulomatous disease, autosomal 2)	p67 phox	1.0	the levels of the p67 phox subunit that contains the nadph binding site of the nadph oxidase complex 10 were increased in membrane fractions of spinal cord extracts from symptomatic transgenic sod1 g93a mice fig 1 c indicating
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	the levels of the p67 phox subunit that contains the nadph binding site of the nadph oxidase complex 10 were increased in membrane fractions of spinal cord extracts from symptomatic transgenic sod1 g93a mice fig 1 c indicating that this cytosolic subunit did translocate to the plasma membran
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	conversely none of these nadph oxidase alterations were seen in age matched nontransgenic littermates fig 1 a _amp_#x02013; e .
2578	CYBB	cytochrome b-245, beta polypeptide (chronic granulomatous disease)	gp91 phox	1.0	histological evaluation of the spinal cord of symptomatic transgenic sod1 g93a mice showed numerous gp91 phox positive cells primarily in the gray matter of the anterior horn fig 1 g whereas sparse staining was observed in the spinal cord of age matched nontransgenic controls fig 1 f .
2578	CYBB	cytochrome b-245, beta polypeptide (chronic granulomatous disease)	gp91 phox	1.0	consistent with nadph oxidase expression by professional phagocytes confocal microscopy demonstrated the colocalization of the gp91 phox subunit with a microglial marker the ricinus communis agglutinin lectin fig 1 h _amp_#x02013; j ; no gp91 phox colocalization was detected with the motor neuron marker nonphosphorylated neurofilament
2578	CYBB	cytochrome b-245, beta polypeptide (chronic granulomatous disease)	gp91 phox	1.0	subunit with a microglial marker the ricinus communis agglutinin lectin fig 1 h _amp_#x02013; j ; no gp91 phox colocalization was detected with the motor neuron marker nonphosphorylated neurofilament heavy chain or with the astrocyte marker glial fibrillary acid protein data not shown .
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	consistent with nadph oxidase expression by professional phagocytes confocal microscopy demonstrated the colocalization of the gp91 phox subunit with a microglial marker the ricinus communis agglutinin lectin fig 1 h _amp_#x02013
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	nadph oxidase causes protein oxidation in transgenic sod1 g93a mice.
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	we further characterized the status of spinal cord nadph oxidase in transgenic sod1 g93a mice by probing for formation of ros and evidence of protein oxidation.
2578	CYBB	cytochrome b-245, beta polypeptide (chronic granulomatous disease)	gp91 phox	1.0	in contrast in symptomatic transgenic sod1 g93a mice carrying the wild type gp91 phox allele sod g93a /gp91 phox+ spinal cord ethidium fluorescence was intense fig 1 l and coincided anatomically with the areas of gp91 phox expression fig 1 g and microglial activation fig 6 .
2578	CYBB	cytochrome b-245, beta polypeptide (chronic granulomatous disease)	gp91 phox	1.0	+ spinal cord ethidium fluorescence was intense fig 1 l and coincided anatomically with the areas of gp91 phox expression fig 1 g and microglial activation fig 6 .
2578	CYBB	cytochrome b-245, beta polypeptide (chronic granulomatous disease)	gp91 phox	1.0	symptomatic transgenic sod1 g93a /gp91 phox+ mice but not age matched sod1 g93a /gp91 phox_amp_#x02212; mice had increased levels of spinal cord protein carbonyl adducts compared with nontransgenic controls expressing either wild type or null
2578	CYBB	cytochrome b-245, beta polypeptide (chronic granulomatous disease)	gp91 phox	1.0	but not age matched sod1 g93a /gp91 phox_amp_#x02212; mice had increased levels of spinal cord protein carbonyl adducts compared with nontransgenic controls expressing either wild type or null mutant gp91 phox fig 1 n .
2578	CYBB	cytochrome b-245, beta polypeptide (chronic granulomatous disease)	gp91 phox	1.0	immunohistochemically the most robust labeling for protein carbonyl adducts occurred in spinal cord sections from sod1 g93a /gp91 phox+ mice at the level of cells with mixed morphology including large motor neurons fig 1 o _amp_#x02013; q .
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	nadph oxidase induction and neuronal protein carbonylation in sporadic als.
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	we then sought to determine whether the nadph oxidase alterations identified in transgenic sod1 g93a mice were also present in human sporadic als the most common form of the disease 1 .
2578	CYBB	cytochrome b-245, beta polypeptide (chronic granulomatous disease)	gp91 phox	1.0	consistent with the mouse data gp91 phox content was low fig 2 a and b and its immunoreactivity was faint in control postmortem spinal cords fig 2 d whereas gp91 phox content was _amp_#x02248;3 fold higher and its immunoreactivity robust in sporadic als spinal cords fig 2 e .
2578	CYBB	cytochrome b-245, beta polypeptide (chronic granulomatous disease)	gp91 phox	1.0	in the latter gp91 phox positive cells colocalized with the microglial associated antigen cd68 fig 2 f and were identified in all of the typical als loci of neurodegeneration including the anterior horn and the lateral cort
2578	CYBB	cytochrome b-245, beta polypeptide (chronic granulomatous disease)	gp91 phox	1.0	deletion of gp91 phox mitigates the disease phenotype in transgenic sod1 g93a mice.
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	next we explored the contribution of nadph oxidase activation on the disease phenotype in the sod1 g93a mouse model of als.
2578	CYBB	cytochrome b-245, beta polypeptide (chronic granulomatous disease)	gp91 phox	1.0	transgenic sod1 g93a /gp91 phox_amp_#x02212; mice reached end stage paralysis defined as a loss of the righting reflex later than their transgenic sod1 g93a /gp91 phox+ counterparts fig 3 a which resulted in a longer lifespan of transgenic sod1 g93a /gp91 phox_amp_#x02212; mice log rank test = 15.3; p _amp_#x0003c; 0.001 .
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	in addition to the prolonged survival inactivation of nadph oxidase did mitigate neurodegeneration.
2578	CYBB	cytochrome b-245, beta polypeptide (chronic granulomatous disease)	gp91 phox	1.0	compared with end stage transgenic sod1 g93a /gp91 phox+ mice age matched transgenic sod1 g93a /gp91 phox_amp_#x02212; mice had _amp_#x02248;50% more anterior horn motor neurons in the spinal cord fig 3 b _amp_#x02013; e and myelinated axons in the fifth
2578	CYBB	cytochrome b-245, beta polypeptide (chronic granulomatous disease)	gp91 phox	1.0	spinal cord microgliosis evidenced by macrophage antigen complex 1 immunostaining and levels of the glial cytokine il 1_amp_#x003b2; did not differ between age matched transgenic sod1 g93a /gp91 phox+ mice and sod1 g93a /gp91 phox_amp_#x02212; mice fig 7 which is published as supporting information on the pnas web site .
2578	CYBB	cytochrome b-245, beta polypeptide (chronic granulomatous disease)	gp91 phox	1.0	also not affected by the deficit of gp91 phox were the levels of human sod1 in transgenic sod1 g93a mice fig 7 or the size of muscle fibers in the fibularis and peroneus longus muscles in nontransgenic mice fig 3 t .
7577	MYH7	myosin, heavy chain 7, cardiac muscle, beta	myosin heavy chain	1.0	the selected muscles are mainly composed of fast twitch fibers and by immunostaining for myosin heavy chain we did not observe any obvious alteration in the makeup of muscle fiber types among the different mouse groups fig 7 .
5464	IGF1	insulin-like growth factor 1 (somatomedin C)	insulin like growth factor 1	1.0	nadph oxidase impairs the insulin like growth factor 1 igf1 /akt pathway in transgenic sod1 g93a mice.
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	nadph oxidase impairs the insulin like growth factor 1 igf1 /akt pathway in transgenic sod1 g93a mice.
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	we then explored whether nadph oxidase mediated protein modifications might promote neurodegeneration in als by damaging essential surviving pathways for motor neurons such as igf1.
2578	CYBB	cytochrome b-245, beta polypeptide (chronic granulomatous disease)	gp91 phox	1.0	however protein carbonyl adducts were evident in the _amp_#x003b1; chain of the igf1 tyrosine kinase cognate receptor in the spinal cord of symptomatic transgenic sod1 g93a /gp91 phox+ mice fig 4 a and b ; similar results were obtained for the _amp_#x003b2; chain of igf1 receptor data not shown .
2578	CYBB	cytochrome b-245, beta polypeptide (chronic granulomatous disease)	gp91 phox	1.0	however there were fewer phospho igf1 receptor immunoreactive cells in spinal cord sections from symptomatic transgenic sod1 g93a /gp91 phox+ mice than from age matched sod1 g93a /gp91 phox_amp_#x02212; mice fig 4 c _amp_#x02013; e .
2578	CYBB	cytochrome b-245, beta polypeptide (chronic granulomatous disease)	gp91 phox	1.0	as fewer cells that were immunoreactive for a downstream target of akt phospho bad fig 4 h _amp_#x02013; j and smaller phospho bad:total bad ratios fig 4 k and l in symptomatic transgenic sod1 g93a /gp91 phox+ mice compared with their age matched sod1 g93a /gp91 phox_amp_#x02212; counterparts.
2578	CYBB	cytochrome b-245, beta polypeptide (chronic granulomatous disease)	gp91 phox	1.0	these data further support the idea that oxidative modification of igf1 receptor in symptomatic transgenic sod1 g93a /gp91 phox+ mice is associated with a range of molecular perturbations.
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	to test the idea that nadph oxidase derived ros could impair igf1 pathway function an in vitro cell system using the neuron like cell lines sh sy5y and imr32 was used.
1516	CAT	catalase	catalase	1.0	to conditioned medium containing 0.1 milliunits/ml glucose oxidase generating an average stable concentration of 75 _amp_#x003bc;m h 2 o 2 fig 5 e ; this effect was abolished by adding 1 000 units/ml catalase to the medium data not shown .
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	however both the alteration of igf1 mediated akt phosphorylation and the loss of cell viability mediated by lps activated microglia were counteracted by the specific nadph oxidase inhibitor apocynin fig 5 c d and f .
2578	CYBB	cytochrome b-245, beta polypeptide (chronic granulomatous disease)	gp91 phox	1.0	germane to the molecular basis of this deleterious effect on motor neurons is our finding that virtually all spinal cord microglial cells express the gp91 phox subunit of the oxidant producing enzyme nadph oxidase fig 1 .
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	germane to the molecular basis of this deleterious effect on motor neurons is our finding that virtually all spinal cord microglial cells express the gp91 phox subunit of the oxidant producing enzyme nadph oxidase fig 1 .
2578	CYBB	cytochrome b-245, beta polypeptide (chronic granulomatous disease)	gp91 phox	1.0	agreeing with the fact that in nonactivated phagocytes nadph oxidase is quiescent 7 gp91 phox positive cells in spinal cords from 1 to 4 month old nontransgenic mice had a morphology of resting microglia and did not seem to produce ros figs 1 and 6 .
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	agreeing with the fact that in nonactivated phagocytes nadph oxidase is quiescent 7 gp91 phox positive cells in spinal cords from 1 to 4 month old nontransgenic mice had a morphology of resting microglia and did not seem to produce ros figs 1 and 6 .
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	conversely in transgenic sod1 g93a mice paralleling the worsening of the als phenotype there was an intensification of spinal cord microgliosis accompanied by an up regulation and activation of nadph oxidase.
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	corroborating this view are the levels of protein carbonyls which were markedly elevated in spinal cord extracts of symptomatic transgenic sod1 g93a mice for the most part in a nadph oxidase dependent manner fig 1 .
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	evidence of microgliosis nadph oxidase up regulation and protein carbonylation was also found in postmortem spinal cords from human sporadic als cases fig 2 supporting the conclusion that the occurrence of inflammation mediated oxidative
2578	CYBB	cytochrome b-245, beta polypeptide (chronic granulomatous disease)	gp91 phox	1.0	our results also show that abrogation of the gp91 phox subunit of nadph oxidase in transgenic sod1 g93a mice eliminates the production of microglial derived ros fig 1 m and importantly prolongs survival and retards neurodegeneration in this als model fig
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	our results also show that abrogation of the gp91 phox subunit of nadph oxidase in transgenic sod1 g93a mice eliminates the production of microglial derived ros fig 1 m and importantly prolongs survival and retards neurodegeneration in this als model fig 3 .
2578	CYBB	cytochrome b-245, beta polypeptide (chronic granulomatous disease)	gp91 phox	1.0	deletion of gp91 phox in transgenic sod1 g93a mice did not alter the spinal cord microglial response or the expression of human sod1 in transgenic sod1 g93a mice fig 7 which is a known determinant of disease severity in t
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	consequently the attenuated phenotype seen in transgenic sod1 g93a /gp91 phox_amp_#x02212; mice is attributable to the lack of nadph oxidase activity and not to either an impaired microglial response or expression of the human sod1 g93a transgene.
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	these data provide compelling evidence that nadph oxidase contributes to the degeneration of motor neurons in als.
2578	CYBB	cytochrome b-245, beta polypeptide (chronic granulomatous disease)	gp91 phox	1.0	however the magnitude of benefit afforded by gp91 phox deletion in transgenic sod1 g93a mice argues that targeting neuroinflammation by inhibiting just one of its mediators such as nadph oxidase may not be sufficient to produce robust and lasting neuropr
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	however the magnitude of benefit afforded by gp91 phox deletion in transgenic sod1 g93a mice argues that targeting neuroinflammation by inhibiting just one of its mediators such as nadph oxidase may not be sufficient to produce robust and lasting neuroprotection in als patients.
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	all cells not motor neurons only which are located in the vicinity of activated microglia may indiscriminately have their plasma membrane proteins and lipids damaged by nadph oxidase derived ros.
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	in this study we indeed found that receptors for igf1 were primarily expressed on motor neurons in mouse spinal cords fig 8 and that the igf1 signaling pathway was impaired by a nadph oxidase dependent mechanism in symptomatic transgenic sod1 g93a mice fig 4 .
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	although igf1 per se did not seem to be damaged by inflammation nadph oxidase did stimulate the oxidative modification of igf1 receptors fig 4 .
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	ggregate show that several molecular events that are normally elicited by ligation of the igf1 receptor including autophosphorylation and akt phosphorylation were indeed abated by ros in a microglial nadph oxidase dependent manner.
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	our data also show that microglial nadph oxidase by impairing the igf1 signaling pathway renders sh sy5y cells in our in vitro system more prone to die upon exposure to a hostile environment such as that emulated by lps activated microglial conditi
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	in our study however we did not find any evidence that the rescue of the igf1 pathway by abrogating nadph oxidase was associated with muscle hypertrophy fig 3 .
2578	CYBB	cytochrome b-245, beta polypeptide (chronic granulomatous disease)	gp91 phox	1.0	nevertheless whether transgenic sod1 g93a mice carrying the gp91 phox null mutation reach end stage paralysis later and exhibit an attenuated neurodegenerative process because of some effects at the skeletal muscle level is an interesting possibility that cannot be exc
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	microglial nadph oxidase stimulates carbonylation of spinal cord motor neurons in transgenic sod1 g93a mice.
2578	CYBB	cytochrome b-245, beta polypeptide (chronic granulomatous disease)	gp91 phox	1.0	a _amp_#x02013; e spinal cord gp91 phox mrna a and d and protein b and e in 1 month old asymptomatic to 4 month old end stage transgenic sod1 more ...
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	nadph oxidase is up regulated and associated with motor neuron carbonylation in the spinal cord of sporadic als patients.
2578	CYBB	cytochrome b-245, beta polypeptide (chronic granulomatous disease)	gp91 phox	1.0	a and b immunoblots and bar graph for gp91 phox using spinal cord extracts from six normal controls and six age matched als patients.
2578	CYBB	cytochrome b-245, beta polypeptide (chronic granulomatous disease)	gp91 phox	1.0	deletion of gp91 phox increases lifespan and lessens neurodegeneration in transgenic sod1 g93a mice.
2578	CYBB	cytochrome b-245, beta polypeptide (chronic granulomatous disease)	gp91 phox	1.0	a survival comparison of transgenic sod1 g93a /gp91 phox+ mice red 122.0 _amp_#x000b1; 1.7 days; n = 19 and transgenic sod1 g93a /gp91 phox_amp_#x02212; littermates more ...
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	modulation of the igf1/akt pathway by nadph oxidase derived ros.
5464	IGF1	insulin-like growth factor 1 (somatomedin C)	insulin like growth factor 1	1.0	ros reactive oxygen species sod1 superoxide dismutase 1 igf1 insulin like growth factor 1
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	superoxide dismutase 1	1.0	ros reactive oxygen species sod1 superoxide dismutase 1 igf1 insulin like growth factor 1
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	superoxide dismutase 1	1.0	insights into its neurodegenerative mechanisms followed the discovery that dominant mutations in the gene for superoxide dismutase 1 sod1 cause familial als 2 3 .
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	among the microglia derived mediators that could promote neurodegeneration are reactive oxygen species ros produced by the enzyme nadph oxidase complex 7 .
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	in light of these facts we undertook the study of nadph oxidase in both human als and one of its genetic models.
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	our results for both human and mouse postmortem tissues indicate that spinal cord microgliosis in als is accompanied with an up regulation of nadph oxidase.
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	furthermore by using mutant deficient mice in functional nadph oxidase as well as in neuron like cell culture systems we provide compelling evidence that supports the concept that this microglial ros generating enzymatic complex promotes spinal cord motor neuron degener