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PMID	15572176 ( )
Title	A role for astrocytes in motor neuron loss in amyotrophic lateral sclerosis.
Abstract	A strong glial reaction typically surrounds the affected upper and lower motor neurons and degenerating descending tracts of ALS patients. Reactive astrocytes in ALS contain protein inclusions, express inflammatory makers such as the inducible forms of nitric oxide synthase (iNOS) and cyclooxygenase (COX-2), display nitrotyrosine immunoreactivity and downregulate the glutamate transporter EAAT2. In this review, we discuss the evidence sustaining an active role for astrocytes in the induction and propagation of motor neuron loss in ALS. Available evidence supports the view that glial activation could be initiated by proinflammatory mediators secreted by motor neurons in response to injury, axotomy or muscular pathology. In turn, reactive astrocytes produce nitric oxide and peroxynitrite, which cause mitochondrial damage in cultured neurons and trigger apoptosis in motor neurons. Astrocytes may also contribute to the excitotoxic damage of motor neurons by decreasing glutamate transport or actively releasing the excitotoxic amino acid. In addition, reactive astrocytes secrete pro-apoptotic mediators, such as nerve growth factor (NGF) or Fas-ligand, a mechanism that may serve to eliminate vulnerable motor neurons. The comprehensive understanding of the interactions between motor neurons and glia in ALS may lead to a more accurate theory of the pathogenesis of the disease. Investigaciones Biologicas Clemente Estable, Avenida Italia 3318-CP 11600, Montevideo, Uruguay. lbarb@iibce.edu.uy

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
11917	TNFRSF1B	tumor necrosis factor receptor superfamily, member 1B	32	p75 \| NTR \|
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	28	SOD1 \| SOD-1 \| SOD1-containing \| superoxide dismutase \| SOD-mimetic \|
7808	NGF	nerve growth factor (beta polypeptide)	23	nerve growth factor \| NGF \|
10940	SLC1A2	solute carrier family 1 (glial high affinity glutamate transporter), member 2	13	GLT-1 \| glt1 \| EAAT2 \| GLT1 \| glt 1 \|
9605	PTGS2	prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase)	12	COX-2 \| cox 2 \|
7873	NOS2A	nitric oxide synthase 2A (inducible, hepatocytes)	11	iNOS \| nitric oxide synthase \|
6018	IL6	interleukin 6 (interferon, beta 2)	10	IL-6 \| il 6 \|
11920	FAS	Fas (TNF receptor superfamily, member 6)	9	Fas \| Fas-ligand \|
11936	FASLG	Fas ligand (TNF superfamily, member 6)	8	FasL \| fas ligand \|
4235	GFAP	glial fibrillary acidic protein	8	glial fibrillary acidic protein \| GFAP \|
7872	NOS1	nitric oxide synthase 1 (neuronal)	6	NOS \| nNOS \|
8024	NTF4	neurotrophin 4	4	NT-4 \| nt 4/5 \| NT-4/5 \|
8031	NTRK1	neurotrophic tyrosine kinase, receptor, type 1	4	TrkA \| Trk \|
1033	BDNF	brain-derived neurotrophic factor	4	neurotrophin \| BDNF \|
6876	MAPK14	mitogen-activated protein kinase 14	3	p38 \| p38 mitogen activated protein kinase \|
4931	HLA-A	major histocompatibility complex, class I, A	2	MHC \|
1509	CASP8	caspase 8, apoptosis-related cysteine peptidase	2	caspase 8 \| caspase-8 \|
5464	IGF1	insulin-like growth factor 1 (somatomedin C)	2	IGF-1 \|
11892	TNF	tumor necrosis factor (TNF superfamily, member 2)	2	TNF-A \|
5438	IFNG	interferon, gamma	2	IFN-G \| interferon gamma \|
6081	INS	insulin	1	insulin \|
4274	GJA1	gap junction protein, alpha 1, 43kDa	1	Cx43 \|
10496	S100A6	S100 calcium binding protein A6	1	S100A6 \|
1504	CASP3	caspase 3, apoptosis-related cysteine peptidase	1	caspase 3 \|
8023	NTF3	neurotrophin 3	1	NT-3 \|
11919	CD40	CD40 molecule, TNF receptor superfamily member 5	1	tumor necrosis factor receptor superfamily \|
10941	SLC1A3	solute carrier family 1 (glial high affinity glutamate transporter), member 3	1	EAAT1 \|

Targets by SciMiner Full list

HUGO ID	Symbol	Name	ActualStr	Score	FlankingText
7873	NOS2A	nitric oxide synthase 2A (inducible, hepatocytes)	iNOS	2.7	such as the inducible forms of nitric oxide synthase (iNOS) iNOS and cyclooxygenase (COX-2), COX-2 display nitrotyrosine immunoreactivity and downregulate the
9605	PTGS2	prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase)	COX-2	1.0	forms of nitric oxide synthase (iNOS) iNOS and cyclooxygenase (COX-2), COX-2 display nitrotyrosine immunoreactivity and downregulate the glutamate transporter EAAT2
10940	SLC1A2	solute carrier family 1 (glial high affinity glutamate transporter), member 2	EAAT2	2.8	(COX-2), COX-2 display nitrotyrosine immunoreactivity and downregulate the glutamate transporter EAAT2
7808	NGF	nerve growth factor (beta polypeptide)	NGF	1.2	astrocytes secrete pro-apoptotic mediators such as nerve growth factor (NGF) NGF or Fas-ligand a mechanism that may serve to eliminate vulnerable
11920	FAS	Fas (TNF receptor superfamily, member 6)	Fas-ligand	0.6	pro-apoptotic mediators such as nerve growth factor (NGF) NGF or Fas-ligand a mechanism that may serve to eliminate vulnerable motor neurons
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD-1	2.4	mutations in the gene encoding copper zinc superoxide dismutase (SOD-1) SOD-1 106
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD-1	2.4	the disease carrying the expression of high levels of mutated SOD-1 genes
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD-1	2.4	Toxicity of mutant SOD-1 involves a dominant gain-of-function rather than simply diminished superoxide-scavenging activity
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD-1	2.4	Spinal motor neurons express high levels of mutant SOD-1 which might explain the selective vulnerability of these neurons
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD-1	2.4	However current evidence indicates that ALS-linked SOD-1 mutations must be expressed in both neuronal and non-neuronal cells
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD-1	2.4	spinal cord nerve or skeletal muscle are required for mutated SOD-1 to initiate neurodegeneration in ALS
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD-1	2.4	of mixtures of normal cells and cells expressing ALS mutant SOD-1 showed that motor neuron degeneration is not necessarily associated with
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD-1	2.4	neuron degeneration is not necessarily associated with the expression of SOD-1 mutations in the motor neuron per se but rather with
4235	GFAP	glial fibrillary acidic protein	GFAP	2.5	processes with increased content of glial fibrillary acidic protein (GFAP) GFAP
4235	GFAP	glial fibrillary acidic protein	GFAP	2.5	Reactive astrocytes in ALS show increased immunoreactivity for GFAP and the calcium binding protein S100_amp_#x3b2 85 and express inflammatory
9605	PTGS2	prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase)	COX-2	1.0	binding protein S100_amp_#x3b2 85 and express inflammatory makers such as COX-2 81 iNOS and neuronal NOS 5 and 115
7873	NOS2A	nitric oxide synthase 2A (inducible, hepatocytes)	iNOS	2.7	S100_amp_#x3b2 85 and express inflammatory makers such as COX-2 81 iNOS and neuronal NOS 5 and 115
7872	NOS1	nitric oxide synthase 1 (neuronal)	NOS	2.7	express inflammatory makers such as COX-2 81 iNOS and neuronal NOS 5 and 115
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD-1	2.4	animal models of ALS including mice and rats carrying different SOD-1 mutations
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD-1	2.4	In the case of mice expressing the G85R SOD-1 mutation astrocytes display major morphological and functional changes characterized by
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD1-containing	1.9	major morphological and functional changes characterized by the appearance of SOD1-containing aggregates and decreased expression of glial glutamate transporter GLT-1 18
10940	SLC1A2	solute carrier family 1 (glial high affinity glutamate transporter), member 2	GLT-1	2.8	of SOD1-containing aggregates and decreased expression of glial glutamate transporter GLT-1 18
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD-1	2.4	However the selective expression of the equivalent murine of G86R SOD-1 mutation in astroglia under the control of a GFAP promoter
4235	GFAP	glial fibrillary acidic protein	GFAP	2.5	G86R SOD-1 mutation in astroglia under the control of a GFAP promoter failed to induce motor neuron loss and disease 52
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD-1	2.4	and disease 52 indicating that glial pathology induced by mutant SOD-1 is not sufficient to initiate neurodegeneration
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD-1	2.4	Thus the selective expression of SOD-1 mutations in glial cells cannot explain per se the striking
10496	S100A6	S100 calcium binding protein A6	S100A6	1.4	G93A mice also upregulate the expression of the calcium-binding protein S100A6 63 as well as iNOS and become immunoreactive for nitrotyrosine
7873	NOS2A	nitric oxide synthase 2A (inducible, hepatocytes)	iNOS	2.7	expression of the calcium-binding protein S100A6 63 as well as iNOS and become immunoreactive for nitrotyrosine 3 and 116
6876	MAPK14	mitogen-activated protein kinase 14	p38	1.2	late stages of the disease express the activated form of p38 mitogen-activated protein kinase 130 which is stimulated by nitric oxide
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD-1	2.4	earlier and more evident astrocytic alterations compared to the G93A SOD-1 mice
10940	SLC1A2	solute carrier family 1 (glial high affinity glutamate transporter), member 2	GLT-1	2.8	the neuropil and with a striking focal loss of the GLT-1 glutamate transporter in the ventral horn
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD-1	2.4	present protein aggregates such as Lewy body-like hyaline inclusions containing SOD-1 are not restricted to motor neurons but are also abundant
4235	GFAP	glial fibrillary acidic protein	GFAP	2.5	number of astrocytes 95 and 111 and the upregulation of GFAP and calcium-binding protein S100_amp_#x3b2 expression 138
4235	GFAP	glial fibrillary acidic protein	GFAP	2.5	in motor neurons and increased number of process-bearing astrocytes over-expressing GFAP in the anterior horn 28
11920	FAS	Fas (TNF receptor superfamily, member 6)	Fas	0.6	by motor neurons in response to trophic factor deprivation 35 Fas pathway activation 101 or loading with zinc-deficient SOD-1 36
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD-1	2.4	deprivation 35 Fas pathway activation 101 or loading with zinc-deficient SOD-1 36
4235	GFAP	glial fibrillary acidic protein	GFAP	2.5	changes characterized by the appearance of process-bearing cells displaying intense GFAP iNOS and nitrotyrosine immunoreactivity 19 and 20
7873	NOS2A	nitric oxide synthase 2A (inducible, hepatocytes)	iNOS	2.7	characterized by the appearance of process-bearing cells displaying intense GFAP iNOS and nitrotyrosine immunoreactivity 19 and 20
7873	NOS2A	nitric oxide synthase 2A (inducible, hepatocytes)	iNOS	2.7	LPS stimulated iNOS expression and nitrotyrosine formation suggesting a role for peroxynitrite in
4274	GJA1	gap junction protein, alpha 1, 43kDa	Cx43	1.3	example astrocytes are extensively coupled by gap junctions of the Cx43 connexin subtype which allows intercellular diffusion of ions and signaling
7872	NOS1	nitric oxide synthase 1 (neuronal)	NOS	2.7	In cultured astrocytes the induction of NOS by pro-inflammatory stimulus or the exposure of astrocyte monolayers to
4235	GFAP	glial fibrillary acidic protein	GFAP	2.5	This is followed by a sustained increase in GFAP synthesis lasting for several days 129
7872	NOS1	nitric oxide synthase 1 (neuronal)	NOS	2.7	histocompatibility complex-encoded antigens 89 interferon gamma 70 and 89 and NOS 70 have been found elevated in motor neurons after nerve
5438	IFNG	interferon, gamma	IFN-G	1.6	Cytokines such as interferon-_amp_#x3b3 (IFN-_amp_#x3b3;) IFN-_amp_#x3b3 are among the most potent inducers of class II MHC
4931	HLA-A	major histocompatibility complex, class I, A	MHC	1.5	IFN-_amp_#x3b3 are among the most potent inducers of class II MHC expression in astrocytes 31
4931	HLA-A	major histocompatibility complex, class I, A	MHC	1.5	cytokines neurotransmitters and neuropeptides are known to induce class II MHC suggesting a scenario in which damaged motor neurons releasing different
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD-1	2.4	showing that astrocyte and microglia activation around motor neurons in SOD-1 G93A mice occurs after the onset of distal axon degeneration
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD-1	2.4	for motor neurons modulating astrocytes reactivity was provided in G93A SOD-1 mice expressing increased levels of insulin growth factor-1 (IGF-1) IGF-1
5464	IGF1	insulin-like growth factor 1 (somatomedin C)	IGF-1	0.3	SOD-1 mice expressing increased levels of insulin growth factor-1 (IGF-1) IGF-1 in spinal motor neurons and skeletal muscle 67
5464	IGF1	insulin-like growth factor 1 (somatomedin C)	IGF-1	0.3	whether these effects are due to an increased release of IGF-1 to the surrounding neuropil targeting glial cells or to a
10940	SLC1A2	solute carrier family 1 (glial high affinity glutamate transporter), member 2	EAAT2	2.8	fluid and a selective reduction of the astrocytic glutamate transporter EAAT2 (GLT1), GLT1 giving support to the excitotoxic hypothesis of motor
10940	SLC1A2	solute carrier family 1 (glial high affinity glutamate transporter), member 2	GLT1	2.8	a selective reduction of the astrocytic glutamate transporter EAAT2 (GLT1), GLT1 giving support to the excitotoxic hypothesis of motor neuron degeneration
10940	SLC1A2	solute carrier family 1 (glial high affinity glutamate transporter), member 2	EAAT2	2.8	In patients with ALS EAAT2 transporters are decreased or defective 108 and 114 which is
10940	SLC1A2	solute carrier family 1 (glial high affinity glutamate transporter), member 2	EAAT2	2.8	Significant loss of the EAAT2 transporters has also been documented in the spinal cord of
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD-1	2.4	transporters has also been documented in the spinal cord of SOD-1 G85R transgenic mice 18 and G93A transgenic rats 62
10941	SLC1A3	solute carrier family 1 (glial high affinity glutamate transporter), member 3	EAAT1	1.3	In contrast neither EAAT1 nor EAAT2 transporters seem to be affected in presymptomatic or
10940	SLC1A2	solute carrier family 1 (glial high affinity glutamate transporter), member 2	EAAT2	2.8	In contrast neither EAAT1 nor EAAT2 transporters seem to be affected in presymptomatic or symptomatic mice
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD1	1.9	be affected in presymptomatic or symptomatic mice carrying the G93A SOD1 mutation and are characterized by less pronounced tardy astrocyte reactivity
10940	SLC1A2	solute carrier family 1 (glial high affinity glutamate transporter), member 2	EAAT2	2.8	The presence of aberrant mRNA splice variants for EAAT2 in ALS has been hypothesized as a putative cause of
10940	SLC1A2	solute carrier family 1 (glial high affinity glutamate transporter), member 2	EAAT2	2.8	in ALS has been hypothesized as a putative cause of EAAT2 loss 6 and 79
9605	PTGS2	prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase)	COX-2	1.0	For example reactive astrocytes in ALS express COX-2 an enzyme that catalyzes the synthesis of the inflammatory prostaglandin
9605	PTGS2	prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase)	COX-2	1.0	Treatment of ALS mice with the COX-2 inhibitor Celecoxib delayed the onset of the disease and increased
6018	IL6	interleukin 6 (interferon, beta 2)	IL-6	1.6	For example in the CNS interleukin-1_amp_#x3b2 (IL-1_amp_#x3b2;) IL-1_amp_#x3b2 and IL-6 exert a powerful regulation of glial cells 109
6018	IL6	interleukin 6 (interferon, beta 2)	IL-6	1.6	Proinflammatory IL-1_amp_#x3b2 and IL-6 are synthesized by neuroglia during epileptic activity 105 the response
7873	NOS2A	nitric oxide synthase 2A (inducible, hepatocytes)	iNOS	2.7	Interestingly cytokine signaling can induce iNOS COX-2 and NMDA receptor subunit phosphorylation with different consequences in
9605	PTGS2	prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase)	COX-2	1.0	Interestingly cytokine signaling can induce iNOS COX-2 and NMDA receptor subunit phosphorylation with different consequences in glial
7873	NOS2A	nitric oxide synthase 2A (inducible, hepatocytes)	iNOS	2.7	Activation of iNOS in astrocytes by IL-1_amp_#x3b2 potentiates NMDA-mediated neurotoxicity in mixed cortical
11892	TNF	tumor necrosis factor (TNF superfamily, member 2)	TNF-A	1.2	Activation of murine astrocytes with tumour necrosis factor-alpha (TNF-_amp_#x3b1;), TNF-_amp_#x3b1 IL-1_amp_#x3b2 and IFN_amp_#x3b3 induces IL-6 COX-2 and iNOS and makes
6018	IL6	interleukin 6 (interferon, beta 2)	IL-6	1.6	with tumour necrosis factor-alpha (TNF-_amp_#x3b1;), TNF-_amp_#x3b1 IL-1_amp_#x3b2 and IFN_amp_#x3b3 induces IL-6 COX-2 and iNOS and makes the cells vulnerable to undergo
9605	PTGS2	prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase)	COX-2	1.0	tumour necrosis factor-alpha (TNF-_amp_#x3b1;), TNF-_amp_#x3b1 IL-1_amp_#x3b2 and IFN_amp_#x3b3 induces IL-6 COX-2 and iNOS and makes the cells vulnerable to undergo apoptosis
7873	NOS2A	nitric oxide synthase 2A (inducible, hepatocytes)	iNOS	2.7	factor-alpha (TNF-_amp_#x3b1;), TNF-_amp_#x3b1 IL-1_amp_#x3b2 and IFN_amp_#x3b3 induces IL-6 COX-2 and iNOS and makes the cells vulnerable to undergo apoptosis in response
11920	FAS	Fas (TNF receptor superfamily, member 6)	Fas	0.6	makes the cells vulnerable to undergo apoptosis in response to Fas ligand (FasL) FasL 39
11936	FASLG	Fas ligand (TNF superfamily, member 6)	FasL	2.2	vulnerable to undergo apoptosis in response to Fas ligand (FasL) FasL 39
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD1	1.9	recently reported in the spinal cord of chronically LPS-treated mutant SOD1 mice 88
6018	IL6	interleukin 6 (interferon, beta 2)	IL-6	1.6	Activated astrocytes are potent producers of IL-6
6018	IL6	interleukin 6 (interferon, beta 2)	IL-6	1.6	While IL-6 can promote survival and protect neurons from degeneration it can
7873	NOS2A	nitric oxide synthase 2A (inducible, hepatocytes)	iNOS	2.7	In particular induction of iNOS by LPS or cytokines seems to be required for astrocytes
7873	NOS2A	nitric oxide synthase 2A (inducible, hepatocytes)	iNOS	2.7	Inhibition of iNOS by nitro--arginine methyl ester and low concentrations of aminoguanidine prevented
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD-1	2.4	cultured motor neurons undergoing apoptosis 35 and 36 in mutant SOD-1 mice 42 and 116 and in sporadic and familial cases
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD-mimetic	1.9	Mn-TBAP is a membrane permeant SOD-mimetic and peroxynitrite scavenger 40
11936	FASLG	Fas ligand (TNF superfamily, member 6)	FasL	2.2	Cytokines and trophic factors produced by activated astrocytes such as FasL TNF-_amp_#x3b1 and NGF are capable of activating death receptors expressed
11892	TNF	tumor necrosis factor (TNF superfamily, member 2)	TNF-A	1.2	and trophic factors produced by activated astrocytes such as FasL TNF-_amp_#x3b1 and NGF are capable of activating death receptors expressed in
7808	NGF	nerve growth factor (beta polypeptide)	NGF	1.2	factors produced by activated astrocytes such as FasL TNF-_amp_#x3b1 and NGF are capable of activating death receptors expressed in the diseased
11936	FASLG	Fas ligand (TNF superfamily, member 6)	FasL	2.2	Although FasL is induced in reactive astrocytes as well as in microglia
11920	FAS	Fas (TNF receptor superfamily, member 6)	Fas	0.6	Motor neurons co-express Fas and FasL during the embryonic period of naturally occurring cell
11936	FASLG	Fas ligand (TNF superfamily, member 6)	FasL	2.2	Motor neurons co-express Fas and FasL during the embryonic period of naturally occurring cell death however
11920	FAS	Fas (TNF receptor superfamily, member 6)	Fas	0.6	in motoneuron survival were observed in mutant mice deficient for Fas signaling 133
11920	FAS	Fas (TNF receptor superfamily, member 6)	Fas	0.6	In contrast Fas signaling has been implicated in motor neuron death induced by
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD	1.9	Furthermore motor neurons from transgenic mice overexpressing ALS-linked SOD mutations G37R G85R or G93A display an increased susceptibility to
11920	FAS	Fas (TNF receptor superfamily, member 6)	Fas	0.6	mutations G37R G85R or G93A display an increased susceptibility to Fas signaling 99 and 101
11920	FAS	Fas (TNF receptor superfamily, member 6)	Fas	0.6	The apoptotic pathway activated by Fas seems to be specific for motor neurons requiring co-activation of
1509	CASP8	caspase 8, apoptosis-related cysteine peptidase	caspase-8	2.0	seems to be specific for motor neurons requiring co-activation of caspase-8 and p38 as well as the production of nitric oxide
6876	MAPK14	mitogen-activated protein kinase 14	p38	1.2	be specific for motor neurons requiring co-activation of caspase-8 and p38 as well as the production of nitric oxide by neuronal
7872	NOS1	nitric oxide synthase 1 (neuronal)	NOS	2.7	as well as the production of nitric oxide by neuronal NOS 101
7808	NGF	nerve growth factor (beta polypeptide)	NGF	1.2	apoptotic candidate released by astrocytes is nerve growth factor (NGF) NGF
7808	NGF	nerve growth factor (beta polypeptide)	NGF	1.2	Clearly NGF is critical for the differentiation and survival of specific neuronal
7808	NGF	nerve growth factor (beta polypeptide)	NGF	1.2	While NGF can signal through activation of the high affinity TrkA receptor
8031	NTRK1	neurotrophic tyrosine kinase, receptor, type 1	TrkA	1.9	While NGF can signal through activation of the high affinity TrkA receptor it also can activate the non-selective neurotrophin receptor p75
11917	TNFRSF1B	tumor necrosis factor receptor superfamily, member 1B	p75	1.8	TrkA receptor it also can activate the non-selective neurotrophin receptor p75 NTR a member of the tumor necrosis factor receptor superfamily
11917	TNFRSF1B	tumor necrosis factor receptor superfamily, member 1B	NTR	0.5	receptor it also can activate the non-selective neurotrophin receptor p75 NTR a member of the tumor necrosis factor receptor superfamily
7808	NGF	nerve growth factor (beta polypeptide)	NGF	1.2	Motor neurons are generally thought to be unresponsive to NGF because they lack the specific TrkA receptor
8031	NTRK1	neurotrophic tyrosine kinase, receptor, type 1	TrkA	1.9	to be unresponsive to NGF because they lack the specific TrkA receptor
1033	BDNF	brain-derived neurotrophic factor	BDNF	0.3	do respond to other members of the neurotrophin family including BDNF NT-3 and NT-4/5 NT-4 5 123
8023	NTF3	neurotrophin 3	NT-3	0.3	respond to other members of the neurotrophin family including BDNF NT-3 and NT-4/5 NT-4 5 123
8024	NTF4	neurotrophin 4	NT-4/5	1.3	other members of the neurotrophin family including BDNF NT-3 and NT-4/5 NT-4 5 123
8024	NTF4	neurotrophin 4	NT-4	1.3	members of the neurotrophin family including BDNF NT-3 and NT-4/5 NT-4 5 123
11917	TNFRSF1B	tumor necrosis factor receptor superfamily, member 1B	p75	1.8	Signaling through p75 NTR in the absence of the corresponding Trk receptor has
11917	TNFRSF1B	tumor necrosis factor receptor superfamily, member 1B	NTR	0.5	Signaling through p75 NTR in the absence of the corresponding Trk receptor has been
8031	NTRK1	neurotrophic tyrosine kinase, receptor, type 1	Trk	1.9	Signaling through p75 NTR in the absence of the corresponding Trk receptor has been shown to promote apoptosis in specific neuronal
11917	TNFRSF1B	tumor necrosis factor receptor superfamily, member 1B	p75	1.8	Motor neurons express p75 NTR during the embryonic period of naturally occurring cell death
11917	TNFRSF1B	tumor necrosis factor receptor superfamily, member 1B	NTR	0.5	Motor neurons express p75 NTR during the embryonic period of naturally occurring cell death when
11917	TNFRSF1B	tumor necrosis factor receptor superfamily, member 1B	p75	1.8	Although p75 NTR is not present in mature motor neurons the receptor
11917	TNFRSF1B	tumor necrosis factor receptor superfamily, member 1B	NTR	0.5	Although p75 NTR is not present in mature motor neurons the receptor can
11917	TNFRSF1B	tumor necrosis factor receptor superfamily, member 1B	p75	1.8	Moreover p75 NTR is found in motor neurons of ALS patients 80
11917	TNFRSF1B	tumor necrosis factor receptor superfamily, member 1B	NTR	0.5	Moreover p75 NTR is found in motor neurons of ALS patients 80 and
11917	TNFRSF1B	tumor necrosis factor receptor superfamily, member 1B	p75	1.8	receptor might modulate the death of neurons in damaged areas p75 NTR expression can be also observed on reactive astrocytes microglia
11917	TNFRSF1B	tumor necrosis factor receptor superfamily, member 1B	NTR	0.5	might modulate the death of neurons in damaged areas p75 NTR expression can be also observed on reactive astrocytes microglia and
7808	NGF	nerve growth factor (beta polypeptide)	NGF	1.2	in chronic active MS lesions suggesting an additional role for NGF in regulating the immune response in glial cells 135
7808	NGF	nerve growth factor (beta polypeptide)	NGF	1.2	expression and release of several growth factors and cytokines including NGF 33
7808	NGF	nerve growth factor (beta polypeptide)	NGF	1.2	Increased NGF levels have been shown in rodent CNS following experimental lesions
7808	NGF	nerve growth factor (beta polypeptide)	NGF	1.2	Expression of NGF receptors in active multiple sclerosis lesions suggests a role for
7808	NGF	nerve growth factor (beta polypeptide)	NGF	1.2	receptors in active multiple sclerosis lesions suggests a role for NGF in regulating the autoimmune response at both immune and glial
7808	NGF	nerve growth factor (beta polypeptide)	NGF	1.2	However little is known about the expression of NGF in ALS although increased NGF levels were reported in muscle
7808	NGF	nerve growth factor (beta polypeptide)	NGF	1.2	known about the expression of NGF in ALS although increased NGF levels were reported in muscle of ALS patients 72 and
7808	NGF	nerve growth factor (beta polypeptide)	NGF	1.2	Thus it is conceivable that NGF signaling between astrocytes and p75 NTR -expressing motor neurons may
11917	TNFRSF1B	tumor necrosis factor receptor superfamily, member 1B	p75	1.8	Thus it is conceivable that NGF signaling between astrocytes and p75 NTR -expressing motor neurons may contribute to the induction of
11917	TNFRSF1B	tumor necrosis factor receptor superfamily, member 1B	NTR	0.5	it is conceivable that NGF signaling between astrocytes and p75 NTR -expressing motor neurons may contribute to the induction of neuronal
7808	NGF	nerve growth factor (beta polypeptide)	NGF	1.2	We have recently found a prominent increase in NGF immunoreactivity in the neuropil of the anterior horn in symptomatic
11917	TNFRSF1B	tumor necrosis factor receptor superfamily, member 1B	p75	1.8	horn in symptomatic mice carrying the G93A mutation coincident with p75 NTR expression in motor neurons 93 suggesting that increased NGF
11917	TNFRSF1B	tumor necrosis factor receptor superfamily, member 1B	NTR	0.5	in symptomatic mice carrying the G93A mutation coincident with p75 NTR expression in motor neurons 93 suggesting that increased NGF production
7808	NGF	nerve growth factor (beta polypeptide)	NGF	1.2	p75 NTR expression in motor neurons 93 suggesting that increased NGF production may parallel the development of astrocytosis in ALS and
7808	NGF	nerve growth factor (beta polypeptide)	NGF	1.2	also found that reactive astrocytes secrete high molecular forms of NGF which could correspond to the precursors forms of NGF (pro-NGF)
7808	NGF	nerve growth factor (beta polypeptide)	NGF	1.2	of NGF which could correspond to the precursors forms of NGF (pro-NGF) pro-NGF 92
11917	TNFRSF1B	tumor necrosis factor receptor superfamily, member 1B	p75	1.8	Some isoforms of pro-NGF bind with high affinity to p75 NTR and thus induces a specific apoptotic signal even in
11917	TNFRSF1B	tumor necrosis factor receptor superfamily, member 1B	NTR	0.5	Some isoforms of pro-NGF bind with high affinity to p75 NTR and thus induces a specific apoptotic signal even in cells
11917	TNFRSF1B	tumor necrosis factor receptor superfamily, member 1B	p75	1.8	induces a specific apoptotic signal even in cells expressing both p75 NTR and TrkA receptors 76
11917	TNFRSF1B	tumor necrosis factor receptor superfamily, member 1B	NTR	0.5	a specific apoptotic signal even in cells expressing both p75 NTR and TrkA receptors 76
8031	NTRK1	neurotrophic tyrosine kinase, receptor, type 1	TrkA	1.9	apoptotic signal even in cells expressing both p75 NTR and TrkA receptors 76
7808	NGF	nerve growth factor (beta polypeptide)	NGF	1.2	Two recent reports further support a role for a NGF/p75 NGF p75 NTR apoptotic pathway in ALS
11917	TNFRSF1B	tumor necrosis factor receptor superfamily, member 1B	p75	1.8	recent reports further support a role for a NGF/p75 NGF p75 NTR apoptotic pathway in ALS
11917	TNFRSF1B	tumor necrosis factor receptor superfamily, member 1B	NTR	0.5	reports further support a role for a NGF/p75 NGF p75 NTR apoptotic pathway in ALS
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD	1.9	Survival of SOD G93A mice is significantly increased by systemic treatment with an
11917	TNFRSF1B	tumor necrosis factor receptor superfamily, member 1B	p75	1.8	with an antisense peptide nucleic acid construct that targets the p75 NTR gene and inhibits its expression 132
11917	TNFRSF1B	tumor necrosis factor receptor superfamily, member 1B	NTR	0.5	an antisense peptide nucleic acid construct that targets the p75 NTR gene and inhibits its expression 132
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD1	1.9	increase in survival was reported in double transgenic mice expressing SOD1 G93A but lacking p75 NTR 73
11917	TNFRSF1B	tumor necrosis factor receptor superfamily, member 1B	p75	1.8	reported in double transgenic mice expressing SOD1 G93A but lacking p75 NTR 73
11917	TNFRSF1B	tumor necrosis factor receptor superfamily, member 1B	NTR	0.5	in double transgenic mice expressing SOD1 G93A but lacking p75 NTR 73
11917	TNFRSF1B	tumor necrosis factor receptor superfamily, member 1B	p75	1.8	For example the re-expression of p75 NTR and neuronal NOS may help to determine which neurons
11917	TNFRSF1B	tumor necrosis factor receptor superfamily, member 1B	NTR	0.5	For example the re-expression of p75 NTR and neuronal NOS may help to determine which neurons survive
7872	NOS1	nitric oxide synthase 1 (neuronal)	NOS	2.7	For example the re-expression of p75 NTR and neuronal NOS may help to determine which neurons survive or undergo apoptosis
11936	FASLG	Fas ligand (TNF superfamily, member 6)	FasL	2.2	Similarly increased production of either FasL or NGF does not induce motor neuron apoptosis unless nitric
7808	NGF	nerve growth factor (beta polypeptide)	NGF	1.2	Similarly increased production of either FasL or NGF does not induce motor neuron apoptosis unless nitric oxide is
11917	TNFRSF1B	tumor necrosis factor receptor superfamily, member 1B	p75	1.8	induce motor neuron apoptosis unless nitric oxide is produced or p75 NTR is expressed in those neurons
11917	TNFRSF1B	tumor necrosis factor receptor superfamily, member 1B	NTR	0.5	motor neuron apoptosis unless nitric oxide is produced or p75 NTR is expressed in those neurons
7872	NOS1	nitric oxide synthase 1 (neuronal)	nNOS	2.7	damage in motor neuron A which upregulates the expression of nNOS p75 NTR Fas cytokines and trophic factors
11917	TNFRSF1B	tumor necrosis factor receptor superfamily, member 1B	p75	1.8	in motor neuron A which upregulates the expression of nNOS p75 NTR Fas cytokines and trophic factors
11917	TNFRSF1B	tumor necrosis factor receptor superfamily, member 1B	NTR	0.5	motor neuron A which upregulates the expression of nNOS p75 NTR Fas cytokines and trophic factors
11920	FAS	Fas (TNF receptor superfamily, member 6)	Fas	0.6	neuron A which upregulates the expression of nNOS p75 NTR Fas cytokines and trophic factors
7808	NGF	nerve growth factor (beta polypeptide)	NGF	1.2	by producing NO cytokines and pro apoptotic mediators such as NGF or FasL
11936	FASLG	Fas ligand (TNF superfamily, member 6)	FasL	2.2	NO cytokines and pro apoptotic mediators such as NGF or FasL
9605	PTGS2	prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase)	cox 2	1.0	reactive astrocytes in als contain protein inclusions express inflammatory makers such as the inducible forms of nitric oxide synthase inos and cyclooxygenase cox 2 display nitrotyrosine immunoreactivity and downregulate the glutamate transporter eaat2.
7873	NOS2A	nitric oxide synthase 2A (inducible, hepatocytes)	nitric oxide synthase	1.0	reactive astrocytes in als contain protein inclusions express inflammatory makers such as the inducible forms of nitric oxide synthase inos and cyclooxygenase cox 2 display nitrotyrosine immunoreactivity and downregulate the glutamate transporter eaat2.
7808	NGF	nerve growth factor (beta polypeptide)	nerve growth factor	1.0	in addition reactive astrocytes secrete pro apoptotic mediators such as nerve growth factor ngf or fas ligand a mechanism that may serve to eliminate vulnerable motor neurons.
11936	FASLG	Fas ligand (TNF superfamily, member 6)	fas ligand	1.0	in addition reactive astrocytes secrete pro apoptotic mediators such as nerve growth factor ngf or fas ligand a mechanism that may serve to eliminate vulnerable motor neurons.
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	superoxide dismutase	1.0	about 10% of als cases show familial inheritance 20% of which are caused by mutations in the gene encoding copper zinc superoxide dismutase sod 1 [ 106 ].
4235	GFAP	glial fibrillary acidic protein	glial fibrillary acidic protein	1.0	by proliferating and adopting a reactive phenotype characterized morphologically by hypertrophic nuclei and cell bodies and elaboration of distinct long and thick processes with increased content of glial fibrillary acidic protein gfap .
9605	PTGS2	prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase)	cox 2	1.0	reactive astrocytes in als show increased immunoreactivity for gfap and the calcium binding protein s100_amp_#x3b2; [ 85 ] and express inflammatory makers such as cox 2 [ 81 ] inos and neuronal nos [ 5 and 115 ].
10940	SLC1A2	solute carrier family 1 (glial high affinity glutamate transporter), member 2	glt 1	1.0	g85r sod 1 mutation astrocytes display major morphological and functional changes characterized by the appearance of sod1 containing aggregates and decreased expression of glial glutamate transporter glt 1 [ 18 ].
6876	MAPK14	mitogen-activated protein kinase 14	p38 mitogen activated protein kinase	1.0	in addition hypertrophic spinal cord astrocytes occurring in the late stages of the disease express the activated form of p38 mitogen activated protein kinase [ 130 ] which is stimulated by nitric oxide and inflammatory mediators.
10940	SLC1A2	solute carrier family 1 (glial high affinity glutamate transporter), member 2	glt 1	1.0	howland et al. [ 62 ] found that gliosis coincided with early vacuolization of the neuropil and with a striking focal loss of the glt 1 glutamate transporter in the ventral horn.
5438	IFNG	interferon, gamma	interferon gamma	1.0	some inflammatory molecules such as fibroblast growth factor [ 64 ] major histocompatibility complex encoded antigens [ 89 ] interferon gamma [ 70 and 89 ] and nos [ 70 ] have been found elevated in motor neurons after nerve lesions or spinal cord injury and proposed to signal between motor neurons and glia.
6081	INS	insulin	insulin	1.0	further evidence for a role for motor neurons modulating astrocytes reactivity was provided in g93a sod 1 mice expressing increased levels of insulin growth factor 1 igf 1 in spinal motor neurons and skeletal muscle [ 67 ].
10940	SLC1A2	solute carrier family 1 (glial high affinity glutamate transporter), member 2	glt1	1.0	many als patients have elevated glutamate levels in cerebrospinal fluid and a selective reduction of the astrocytic glutamate transporter eaat2 glt1 giving support to the excitotoxic hypothesis of motor neuron degeneration [ 107 ].
9605	PTGS2	prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase)	cox 2	1.0	for example reactive astrocytes in als express cox 2 an enzyme that catalyzes the synthesis of the inflammatory prostaglandin e2 which in turn stimulates glutamate release from astrocytes.
9605	PTGS2	prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase)	cox 2	1.0	treatment of als mice with the cox 2 inhibitor celecoxib delayed the onset of the disease and increased the survival rates [ 30 ] further suggesting a link between inflammation and excitotoxicity. 4.2.
6018	IL6	interleukin 6 (interferon, beta 2)	il 6	1.0	for example in the cns interleukin 1_amp_#x3b2; il 1_amp_#x3b2; and il 6 exert a powerful regulation of glial cells [ 109 ].
6018	IL6	interleukin 6 (interferon, beta 2)	il 6	1.0	proinflammatory il 1_amp_#x3b2; and il 6 are synthesized by neuroglia during epileptic activity [ 105 ] the response being greater when seizures are associated with neuronal damage suggesting the release of neuronal mediators.
9605	PTGS2	prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase)	cox 2	1.0	interestingly cytokine signaling can induce inos cox 2 and nmda receptor subunit phosphorylation with different consequences in glial and neuronal cells.
9605	PTGS2	prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase)	cox 2	1.0	activation of murine astrocytes with tumour necrosis factor alpha tnf _amp_#x3b1; il 1_amp_#x3b2; and ifn_amp_#x3b3; induces il 6 cox 2 and inos and makes the cells vulnerable to undergo apoptosis in response to fas ligand fasl [ 39 ].
11936	FASLG	Fas ligand (TNF superfamily, member 6)	fas ligand	1.0	f murine astrocytes with tumour necrosis factor alpha tnf _amp_#x3b1; il 1_amp_#x3b2; and ifn_amp_#x3b3; induces il 6 cox 2 and inos and makes the cells vulnerable to undergo apoptosis in response to fas ligand fasl [ 39 ].
6018	IL6	interleukin 6 (interferon, beta 2)	il 6	1.0	activation of murine astrocytes with tumour necrosis factor alpha tnf _amp_#x3b1; il 1_amp_#x3b2; and ifn_amp_#x3b3; induces il 6 cox 2 and inos and makes the cells vulnerable to undergo apoptosis in response to fas ligand fasl [ 39 ].
6018	IL6	interleukin 6 (interferon, beta 2)	il 6	1.0	activated astrocytes are potent producers of il 6.
6018	IL6	interleukin 6 (interferon, beta 2)	il 6	1.0	while il 6 can promote survival and protect neurons from degeneration it can also promote astrocyte proliferation and activation [ 31 ].
1504	CASP3	caspase 3, apoptosis-related cysteine peptidase	caspase 3	1.0	some motor neurons plated on these reactive astrocytes were smaller and displayed immunoreactivity for cleaved caspase 3 suggesting the activation of apoptotic mechanisms.
1509	CASP8	caspase 8, apoptosis-related cysteine peptidase	caspase 8	1.0	the apoptotic pathway activated by fas seems to be specific for motor neurons requiring co activation of caspase 8 and p38 as well as the production of nitric oxide by neuronal nos [ 101 ].
7808	NGF	nerve growth factor (beta polypeptide)	nerve growth factor	1.0	another potential apoptotic candidate released by astrocytes is nerve growth factor ngf .
1033	BDNF	brain-derived neurotrophic factor	neurotrophin	1.0	while ngf can signal through activation of the high affinity trka receptor it also can activate the non selective neurotrophin receptor p75 ntr a member of the tumor necrosis factor receptor superfamily.
11919	CD40	CD40 molecule, TNF receptor superfamily member 5	tumor necrosis factor receptor superfamily	1.0	while ngf can signal through activation of the high affinity trka receptor it also can activate the non selective neurotrophin receptor p75 ntr a member of the tumor necrosis factor receptor superfamily.
1033	BDNF	brain-derived neurotrophic factor	neurotrophin	1.0	however they do respond to other members of the neurotrophin family including bdnf nt 3 and nt 4/5 [ 123 ].
8024	NTF4	neurotrophin 4	nt 4/5	1.0	however they do respond to other members of the neurotrophin family including bdnf nt 3 and nt 4/5 [ 123 ].
8024	NTF4	neurotrophin 4	nt 4/5	1.0	however they do respond to other members of the neurotrophin family including bdnf nt 3 and nt 4/5 [ 123 ].
1033	BDNF	brain-derived neurotrophic factor	neurotrophin	1.0	it has been recently shown that the pro neurotrophin is enriched in the cns [ 38 ] and could be secreted by different cell types [ 56 and 58 ].