Document Information


PMID 17418957  (  )
Title Tumor necrosis factor-alpha induces changes in mitochondrial cellular distribution in motor neurons.
Abstract Motor neuron (MN) mitochondrial abnormalities and elevation in spinal fluid levels of the inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). The mechanism of neuron death in ALS remains unclear, along with the contributions of mitochondrial dysfunction and inflammation in the process. Cell cultures enriched for MN derived from embryonic rat spinal cords were established and directly exposed in vitro to recombinant TNF-alpha for varying lengths of time. Although cytokine exposure for up to 4 days failed to induce MN death, mitochondrial changes were observed shortly after initiating treatment. Our results demonstrate that TNF-alpha induced mitochondrial redistribution toward the soma in MN. We postulate that inflammation may precede, and in fact cause, the mitochondrial changes observed in ALS tissue. Center, One Medical Center Drive, Lebanon, NH 03756, and Department of Biology, Dartmouth College, Hanover 03755, USA. elijah.w.stommel@hitchcock.org

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
11892TNFtumor necrosis factor (TNF superfamily, member 2)68tumor necrosis factor alpha | TNF-A |
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))7SOD1 |
11916TNFRSF1Atumor necrosis factor receptor superfamily, member 1A2p55 |
6081INSinsulin1insulin |
9461PRPHperipherin1peripherin |
2169CNTFciliary neurotrophic factor1CNTF |
7873NOS2Anitric oxide synthase 2A (inducible, hepatocytes)1iNOS |
2770DESdesmin1intermediate filament protein |
11740TFtransferrin1transferrin |
11917TNFRSF1Btumor necrosis factor receptor superfamily, member 1B1p75 |
4232GDNFglial cell derived neurotrophic factor1GDNF |
399ALBalbumin1serum albumin |
6839MAP2microtubule-associated protein 21microtubule associated protein 2 |
7808NGFnerve growth factor (beta polypeptide)1NGF |

 


Targets by SciMiner Full list

HUGO ID Symbol Name ActualStr Score FlankingText
11892TNFtumor necrosis factor (TNF superfamily, member 2)TNF-A1.2fluid levels of the inflammatory cytokine tumor necrosis factor-alpha (TNF-_amp_#x3b1;) TNF-_amp_#x3b1 have been implicated in the pathogenesis of amyotrophic lateral sclerosis
11892TNFtumor necrosis factor (TNF superfamily, member 2)TNF-A1.2cords were established and directly exposed in vitro to recombinant TNF-_amp_#x3b1 for varying lengths of time
11892TNFtumor necrosis factor (TNF superfamily, member 2)TNF-A1.2Our results demonstrate that TNF-_amp_#x3b1 induced mitochondrial redistribution toward the soma in MN
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD10.5the onset of MN degeneration in mice expressing a mutant SOD1 ( Kong and Xu 1998
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD10.5ultrastructural studies of anterior horn cells of ALS patients and SOD1 mouse model show accumulation of mitochondria in the axonal hillock
11892TNFtumor necrosis factor (TNF superfamily, member 2)TNF-A1.2Serum levels of the cytokine tumor necrosis factor-alpha (TNF-_amp_#x3b1;) TNF-_amp_#x3b1 and its soluble receptors have been reported to be elevated
11892TNFtumor necrosis factor (TNF superfamily, member 2)TNF-A1.2In the G93A-SOD1 mouse the TNF-_amp_#x3b1 receptor p55 is upregulated between pre-symptomatic and symptomatic stages of
11916TNFRSF1Atumor necrosis factor receptor superfamily, member 1Ap551.2In the G93A-SOD1 mouse the TNF-_amp_#x3b1 receptor p55 is upregulated between pre-symptomatic and symptomatic stages of disease suggesting
11892TNFtumor necrosis factor (TNF superfamily, member 2)TNF-A1.2upregulated between pre-symptomatic and symptomatic stages of disease suggesting that TNF-_amp_#x3b1 and its receptors may be involved in MN degeneration (
11892TNFtumor necrosis factor (TNF superfamily, member 2)TNF-A1.2TNF-_amp_#x3b1 has been shown to cause or contribute to cell death
11892TNFtumor necrosis factor (TNF superfamily, member 2)TNF-A1.2Previous reports have demonstrated that stimulation of sensitive cells with TNF-_amp_#x3b1 induces abnormal perinuclear clustering of mitochondria from an evenly spread
11892TNFtumor necrosis factor (TNF superfamily, member 2)TNF-A1.2trafficking of mitochondria in MN within neurites is altered by TNF-_amp_#x3b1 an observation that mimics the in vivo histological findings in
11892TNFtumor necrosis factor (TNF superfamily, member 2)TNF-A1.2Because of the reported elevation of TNF-_amp_#x3b1 and its receptors ( Poloni et al 2000 Hensley et
11892TNFtumor necrosis factor (TNF superfamily, member 2)TNF-A1.2setting of ALS and the known positive effects of the TNF-_amp_#x3b1 blocker thalidomide on the progression of ALS in the SOD1
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD10.5TNF-_amp_#x3b1 blocker thalidomide on the progression of ALS in the SOD1 mouse model ( Wong et al 2004 and Kiaei et
11892TNFtumor necrosis factor (TNF superfamily, member 2)TNF-A1.22006 we initiated experiments to study the biological effects of TNF-_amp_#x3b1 on MN in vitro
11892TNFtumor necrosis factor (TNF superfamily, member 2)TNF-A1.2survival axonal transport necrosis and apoptosis have well-documented responses to TNF-_amp_#x3b1 (both both related to apoptosis and cellular migration and have
11892TNFtumor necrosis factor (TNF superfamily, member 2)TNF-A1.2vitro studies specifically to evaluate the responses of mitochondria to TNF-_amp_#x3b1
11917TNFRSF1Btumor necrosis factor receptor superfamily, member 1Bp751.2MNs by positive selection immuno-panning using antibody against the low-affinity p75 NGF receptor (192 192 antibody was a gift of the
7808NGFnerve growth factor (beta polypeptide)NGF0.3by positive selection immuno-panning using antibody against the low-affinity p75 NGF receptor (192 192 antibody was a gift of the E
4232GDNFglial cell derived neurotrophic factorGDNF0.9Invitrogen 10 ng/ml ng ml each of BDNF CNTF and GDNF (Peprotech, Peprotech Rocky Hill NJ USA 100 _amp_#x3bc;g/ml _amp_#x3bc g
2169CNTFciliary neurotrophic factorCNTF0.1B27 (Invitrogen), Invitrogen 10 ng/ml ng ml each of BDNF CNTF and GDNF (Peprotech, Peprotech Rocky Hill NJ USA 100 _amp_#x3bc;g/ml
11892TNFtumor necrosis factor (TNF superfamily, member 2)TNF-A1.2cultures were exposed to 0 or 20 ng/ml ng ml TNF-_amp_#x3b1 (R_amp_#x26;D R_amp_#x26 D Systems Minneapolis MN USA on days 3
11892TNFtumor necrosis factor (TNF superfamily, member 2)TNF-A1.2was also evaluated with exposure to 100 ng/ml ng ml TNF-_amp_#x3b1 using TUNEL staining (DeadEndTM DeadEndTM Fluorometric TUNEL System Promega Madison
11892TNFtumor necrosis factor (TNF superfamily, member 2)TNF-A1.2Doses of 100 ng/ml ng ml or lower of TNF-_amp_#x3b1 were used in all experiments
11892TNFtumor necrosis factor (TNF superfamily, member 2)TNF-A1.2washed three times with the medium cells were treated with TNF-_amp_#x3b1 at 20 ng/ml ng ml in growth medium
11892TNFtumor necrosis factor (TNF superfamily, member 2)TNF-A1.2For the TNF-_amp_#x3b1 cultures and the same conditions 16 cells were counted from
11892TNFtumor necrosis factor (TNF superfamily, member 2)TNF-A1.2were used to determine velocity of mitochondrial transport in both TNF-_amp_#x3b1 -treated and untreated cell populations
11892TNFtumor necrosis factor (TNF superfamily, member 2)TNF-A1.2For the TNF-_amp_#x3b1 treated cells we looked at five cells from three different
11892TNFtumor necrosis factor (TNF superfamily, member 2)TNF-A1.2There were more cells of sufficient clarity for the TNF-_amp_#x3b1 group
11892TNFtumor necrosis factor (TNF superfamily, member 2)TNF-A1.2left fewer wells as controls and treated the rest with TNF-_amp_#x3b1
11892TNFtumor necrosis factor (TNF superfamily, member 2)TNF-A1.2were determined from multiple experiments using 20 ng/ml ng ml TNF-_amp_#x3b1 between 6 and 20 h
11892TNFtumor necrosis factor (TNF superfamily, member 2)TNF-A1.2MN survival and cellular distribution of mitochondria in response to TNF-_amp_#x3b1
11892TNFtumor necrosis factor (TNF superfamily, member 2)TNF-A1.2in MN cultures exposed to 100 ng/ml ng ml of TNF-_amp_#x3b1 appeared similar to untreated cultures based on cell numbers and
11892TNFtumor necrosis factor (TNF superfamily, member 2)TNF-A1.2of multiple neurites (untreated=23.2_amp_#xb1;2.1 untreated=23.2_amp_#xb1 2.1 neurons/mm neurons mm 2 TNF-_amp_#x3b1 =23.9_amp_#xb1 2.7 neurons/mm neurons mm 2
11892TNFtumor necrosis factor (TNF superfamily, member 2)TNF-A1.2the percentage of TUNEL-positive cells was observed after treatment with TNF-_amp_#x3b1 (18_amp_#xb1;4%) 18_amp_#xb1 4% for 2 days at concentrations of 100
11892TNFtumor necrosis factor (TNF superfamily, member 2)TNF-A1.2TNF-_amp_#x3b1 alone was insufficient in inducing MN death in cultures
11892TNFtumor necrosis factor (TNF superfamily, member 2)TNF-A1.2the somas of cells treated with 20 ng/ml ng ml TNF-_amp_#x3b1 ( Fig 2 B D as compared with controls (
11892TNFtumor necrosis factor (TNF superfamily, member 2)TNF-A1.2of mitochondrial movement in neurites of MN during exposure to TNF-_amp_#x3b1
11892TNFtumor necrosis factor (TNF superfamily, member 2)TNF-A1.2and 0.671_amp_#xb1 0.115 _amp_#x3bc;m/s _amp_#x3bc m s for control and TNF-_amp_#x3b1 -treated respectively
11892TNFtumor necrosis factor (TNF superfamily, member 2)TNF-A1.2and 0.704_amp_#xb1 0.117 _amp_#x3bc;m/s _amp_#x3bc m s for control and TNF-_amp_#x3b1 -treated respectively
11892TNFtumor necrosis factor (TNF superfamily, member 2)TNF-A1.2No significant velocity changes were observed with TNF-_amp_#x3b1 treatment as assessed using Student t -test for two-sample comparisons
11892TNFtumor necrosis factor (TNF superfamily, member 2)TNF-A1.21.5 2_amp_#x2013 4 and 6_amp_#x2013 8 h after treatment with TNF-_amp_#x3b1 to evaluate the time-frame that an increase in MT Green
11892TNFtumor necrosis factor (TNF superfamily, member 2)TNF-A1.2the retrograde-moving was observed after 1.5 h of treatment with TNF-_amp_#x3b1 ( Fig 3 B
11892TNFtumor necrosis factor (TNF superfamily, member 2)TNF-A1.2opposed to the exposure to 20 ng/ml ng ml of TNF-_amp_#x3b1 (stacktnf3.avi) stacktnf3.avi at 6 h
11892TNFtumor necrosis factor (TNF superfamily, member 2)TNF-A1.2Retrograde/anterograde Retrograde anterograde neuritic transport ratios in response to TNF-_amp_#x3b1
11892TNFtumor necrosis factor (TNF superfamily, member 2)TNF-A1.2retrograde/anterograde retrograde anterograde mitochondrial movement increases in the presence of TNF-_amp_#x3b1 in vitro
11892TNFtumor necrosis factor (TNF superfamily, member 2)TNF-A1.2In the presence of TNF-_amp_#x3b1 we observed an increase in the retrograde/anterograde retrograde anterograde ratio
11892TNFtumor necrosis factor (TNF superfamily, member 2)TNF-A1.2a unipolar perinuclear cluster has been documented in response to TNF-_amp_#x3b1 in murine L929 cells ( De Vos et al. 1998
11892TNFtumor necrosis factor (TNF superfamily, member 2)TNF-A1.2Our observed effects with TNF-_amp_#x3b1 seem to be greatest at about 4 h and then
11892TNFtumor necrosis factor (TNF superfamily, member 2)TNF-A1.2We are unable to say by what mechanism TNF-_amp_#x3b1 effects the localization and movement of mitochondria in MN
11892TNFtumor necrosis factor (TNF superfamily, member 2)TNF-A1.2We did not see an effect of TNF-_amp_#x3b1 on the average or maximum velocity of anterograde or retrograde
11892TNFtumor necrosis factor (TNF superfamily, member 2)TNF-A1.2the net mitochondrial transport toward the soma in response to TNF-_amp_#x3b1 appears to be related to an increased amount of retrograde
11892TNFtumor necrosis factor (TNF superfamily, member 2)TNF-A1.2ratio of retrograde to anterograde movements the observed changes with TNF-_amp_#x3b1 treatment were significant
11892TNFtumor necrosis factor (TNF superfamily, member 2)TNF-A1.2Whether TNF-_amp_#x3b1 perturbs the ATP distribution in MNs is not known but
11892TNFtumor necrosis factor (TNF superfamily, member 2)TNF-A1.2the ATP distribution in MNs is not known but if TNF-_amp_#x3b1 were able to decrease levels of ATP near the cell
11892TNFtumor necrosis factor (TNF superfamily, member 2)TNF-A1.2TNF-_amp_#x3b1 has been shown to cause or contribute to cell death
11892TNFtumor necrosis factor (TNF superfamily, member 2)TNF-A1.2Previous studies have shown that TNF-_amp_#x3b1 mediates apoptosis in cultured MN and DRG neurons that over-express
11892TNFtumor necrosis factor (TNF superfamily, member 2)TNF-A1.2Recent studies have demonstrated that the TNF-_amp_#x3b1 blocker thalidomide is effective in increasing survival and delaying progression
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD10.5increasing survival and delaying progression of ALS phenotypes in the SOD1 G93A mouse model ( Wong et al 2004 and Kiaei
11892TNFtumor necrosis factor (TNF superfamily, member 2)TNF-A1.2Interestingly TNF-_amp_#x3b1 knockout mice are resistant to some forms of neurodegeneration as
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD10.5( Sriram et al. 2002 yet generation of mice expressing SOD1 G37R or SOD1 G93A mutants in the context of TNF-_amp_#x3b1
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD10.5al. 2002 yet generation of mice expressing SOD1 G37R or SOD1 G93A mutants in the context of TNF-_amp_#x3b1 gene knockout did
11892TNFtumor necrosis factor (TNF superfamily, member 2)TNF-A1.2SOD1 G37R or SOD1 G93A mutants in the context of TNF-_amp_#x3b1 gene knockout did not affect the lifespan or the extent
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD10.5affect the lifespan or the extent of MN loss in SOD1 transgenic mice ( Gowing et al. 2006
11892TNFtumor necrosis factor (TNF superfamily, member 2)TNF-A1.2In the G93A-SOD1 mouse the TNF-_amp_#x3b1 receptor p55 is upregulated between presymptomatic and symptomatic stages of
11916TNFRSF1Atumor necrosis factor receptor superfamily, member 1Ap551.2In the G93A-SOD1 mouse the TNF-_amp_#x3b1 receptor p55 is upregulated between presymptomatic and symptomatic stages of disease suggesting
11892TNFtumor necrosis factor (TNF superfamily, member 2)TNF-A1.2upregulated between presymptomatic and symptomatic stages of disease suggesting that TNF-_amp_#x3b1 and its receptors may connect inflammation to apoptosis in ALS
11892TNFtumor necrosis factor (TNF superfamily, member 2)TNF-A1.2in isolated MNs was affected on the order of hours TNF-_amp_#x3b1 exposure for several days failed to increase the number of
11892TNFtumor necrosis factor (TNF superfamily, member 2)TNF-A1.2The role of TNF-_amp_#x3b1 appears to often require the synergism of other cytokines
11892TNFtumor necrosis factor (TNF superfamily, member 2)TNF-A1.2There is a 20-fold increase in the amount of TNF-_amp_#x3b1 required to kill NSC-34 cells in the absence of LPS-activated
11892TNFtumor necrosis factor (TNF superfamily, member 2)TNF-A1.2indicating that microglia secrete a factor(s) factor s that facilitate TNF-_amp_#x3b1 mediated MN death in vitro ( He et al. 2002
11892TNFtumor necrosis factor (TNF superfamily, member 2)TNF-A1.2Our data suggest that TNF-_amp_#x3b1 alone is not sufficient to cause apoptosis in our isolated
11892TNFtumor necrosis factor (TNF superfamily, member 2)TNF-A1.2of mitochondria closer to the cell body in response to TNF-_amp_#x3b1 could predispose cells to elevated levels of reactive oxygen species
11892TNFtumor necrosis factor (TNF superfamily, member 2)TNF-A1.2shown effects on neuritic transport of mitochondria with the cytokine TNF-_amp_#x3b1
11892TNFtumor necrosis factor (TNF superfamily, member 2)TNF-A1.2The observed redistribution of mitochondria in response to TNF-_amp_#x3b1 is similar to that observed in the MN of ALS
11892TNFtumor necrosis factor (TNF superfamily, member 2)TNF-A1.2disease which has been shown to have elevated levels of TNF-_amp_#x3b1 in the spinal cord and serum
11892TNFtumor necrosis factor (TNF superfamily, member 2)TNF-A1.2necrosis which may require the presence of glial cells for TNF-_amp_#x3b1 to be effective
7873NOS2Anitric oxide synthase 2A (inducible, hepatocytes)iNOS1.0also plan to evaluate apoptosis and necrosis as well as iNOS production in response to a variety of cytokines
11892TNFtumor necrosis factor (TNF superfamily, member 2)tumor necrosis factor alpha1.0motor neuron mn mitochondrial abnormalities and elevation in spinal fluid levels of the inflammatory cytokine tumor necrosis factor alpha tnf _amp_#x3b1; have been implicated in the pathogenesis of amyotrophic lateral sclerosis als .
11892TNFtumor necrosis factor (TNF superfamily, member 2)tumor necrosis factor alpha1.0serum levels of the cytokine tumor necrosis factor alpha tnf _amp_#x3b1; and its soluble receptors have been reported to be elevated in als patients as compared with healthy controls poloni et al 2000 and strong 2003 .
6081INSinsulininsulin1.0vitrogen 10 ng/ml each of bdnf cntf and gdnf peprotech rocky hill nj usa 100 _amp_#x3bc;g/ml transferrin 60 ng/ml progesterone 16 _amp_#x3bc;g/ml putrescine 40 ng/ml sodium selenite 5 _amp_#x3bc;g/ml insulin 1 mm sodium pyruvate 2 mm l glutamine 40 ng/ml triiodo thyronine 1 _amp_#x3bc;g/ml laminin 2.2 _amp_#x3bc;g/ml isobutylmethylxanthine 417 ng/ml forskolin 5 _amp_#x3bc;g/ml n acetyl cysteine 100 u/ml
11740TFtransferrintransferrin1.0neurobasal base media invitrogen carlsbad ca usa was supplemented with b27 invitrogen 10 ng/ml each of bdnf cntf and gdnf peprotech rocky hill nj usa 100 _amp_#x3bc;g/ml transferrin 60 ng/ml progesterone 16 _amp_#x3bc;g/ml putrescine 40 ng/ml sodium selenite 5 _amp_#x3bc;g/ml insulin 1 mm sodium pyruvate 2 mm l glutamine 40 ng/ml triiodo thyronine 1 _amp_#x3bc;g/ml laminin 2.2 _
399ALBalbuminserum albumin1.0triton x 100 0.1% bovine serum albumin 1% and normal goat serum 1% were used to permeate the cells and limit non specific binding.
6839MAP2microtubule-associated protein 2microtubule associated protein 21.0although this characteristic itself is not reliable confirmation of this distinction can be made with immunohistochemical staining where at certain stages of development microtubule associated protein 2 is exclusively located in the somatodendritic domain matus et al. 1986 and the dephosphorylated form of tau 1 is exclusively found in the axons mandell and banker 1996 .
2770DESdesminintermediate filament protein1.0previous studies have shown that tnf _amp_#x3b1; mediates apoptosis in cultured mn and drg neurons that over express the intermediate filament protein peripherin that associates with axonal spheroid inclusions in degenerating mn of als patients robertson et al. 2001 .
9461PRPHperipherinperipherin1.0previous studies have shown that tnf _amp_#x3b1; mediates apoptosis in cultured mn and drg neurons that over express the intermediate filament protein peripherin that associates with axonal spheroid inclusions in degenerating mn of als patients robertson et al. 2001 .
11892TNFtumor necrosis factor (TNF superfamily, member 2)tumor necrosis factor alpha1.0tumor necrosis factor alpha|