Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.6.99.6 (NADPH oxidase)
 10,295 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease, in which activated microglia overexpressing ALS-linked SOD1 mutants (mSOD1) are known to contribute to neuronal death. However, it is unclear how mSOD1 expression affects micoglial activation and subsequently damages neurons. In this study, we created mSOD1-overexpressing BV-2 microglial cell lines. Following TLR2, but not TLR4 stimulation, we observed that overexpression of human SOD1 G93A, L8Q, or G10V mutant, as compared with the wild-type SOD1 or a mock control, significantly enhanced microglial secretion of a neurotoxic cytokine, tumor necrosis factor-alpha (TNF-alpha), which was dependent on the NADPH-oxidase-mediated increased generation of reactive oxygen species (ROS). In further experiments, we demonstrated that mSOD1 expression regulated TNF-alpha secretion at a post-transcriptional level and involved ROS-sensitive TNF-alpha-converting enzymes, e.g. ADAM10 and -17, which shed TNF-alpha from its membrane-anchored precursor. Together with a recent report that the function of SOD1, as a self-regulating redox sensor in NADPH oxidase-dependent ROS production, is lost due to its genetic mutations, we conclude that mSOD1 expression in ALS facilitates microglial neurotoxic inflammatory responses via TLR2, which is mediated by an uncontrolled ROS generation. The link, between mSOD1, innate immunity and NADPH oxidase, offers new opportunities in ALS therapies.
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PMID:Expression of amyotrophic lateral sclerosis-linked SOD1 mutant increases the neurotoxic potential of microglia via TLR2. 1909 52

The mechanisms underlying selective motor neuron degeneration in amyotrophic lateral sclerosis (ALS) remain unknown. There have been several important clinical trials on the treatment of ALS and treatment efficacy studies using mouse (SOD1) models of ALS. The latter revealed that diminished mutant SOD1 expression in the astrocytes delayed microglial activation and slowed disease progression. Dyslipidemia has been reported to have a protective effect in ALS patients. Current evidence has implicated a 43-kDa TAR DNA-binding protein (TDP-43) in the pathologenesis of ALS. Several mutations in TDP-43 were discovered in families with inherited motor neuron disease. Although phase III trials revealed that creatine monohydrate and IGF-1 was not beneficial for patients with ALS, favorable outcomes in SOD1 mice were reported with lithium, NADPH oxidase inhibitor, free-radical scavenger, and ammonium tetrathiomolybdate. Spinal and bulbar muscular atrophy (SBMA) is an adult-onset motor neuron disease affecting only males. Animal studies have revealed that the pathogenesis of SBMA depends on the serum testosterone level and that androgen deprivation mitigates neurodegeneration through inhibition of nuclear accumulation of the pathogenic androgen receptor (AR). Our studies have also identified several candidates for the treatment of SBMA. Selective inhibition of heat shock protein (HSP) facilitates the proteasomal degradation of pathogenic AR, leading to improvements in the signs and symptoms of SBMA mice. Oral administration of sodium butyrate--a histone deacetylase inhibitor--resulted in the improvement of neurological dysfunction in the SBMA mouse model, although its therapeutic dose range is narrow.
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PMID:[Molecular-targeted therapy for motor neuron disease]. 1969 78

Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease. Human neural stem cells (hNSCs) may have the potential to replace lost motor neurons. The therapeutic efficacy of stem cell therapy depends greatly on the survival of grafted stem cell-derived motor neurons in the microenvironment of the spinal cord in ALS. After transplantation of hNSCs into the spinal cords of transgenic ALS rats, morphological analysis reveals that grafted hNSCs differentiate into motor neurons. However, hNSCs degenerate and show signs of nitroxidative damage at the disease end-stage. Using an in vitro coculture system, we systematically assess interactions between microglia and astroglia derived from both nontransgenic rats and transgenic rats expressing human mutant SOD1(G93A) before and after symptomatic disease onset, and determine the effects of such microglia-astroglia interactions on the survival of hNSC-derived motor neurons. We found that ALS microglia, specifically isolated after symptomatic disease onset, are directly toxic to hNSC-derived motor neurons. Furthermore, nontransgenic astrocytes not only lose their protective role in hNSC-derived motor neuron survival in vitro, but also exhibit toxic features when cocultured with mutant SOD1(G93A) microglia. Using inhibitors of inducible nitric oxide synthase and NADPH oxidase, we show that microglia-generated nitric oxide and superoxide partially contribute to motor neuron loss and astrocyte dysfunction in this coculture paradigm. In summary, reactive oxygen/nitrogen species released from overactivated microglia in ALS directly eliminate human neural stem cell-derived motor neurons and reduce the neuroprotective capacities of astrocytes.
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PMID:Mutant SOD1 microglia-generated nitroxidative stress promotes toxicity to human fetal neural stem cell-derived motor neurons through direct damage and noxious interactions with astrocytes. 2367 93

In rats over-expressing SOD1G93A, ventilation is preserved despite significant loss of respiratory motor neurons. Thus, unknown forms of compensatory respiratory plasticity may offset respiratory motor neuron cell death. Although mechanisms of such compensation are unknown, other models of respiratory motor plasticity may provide a conceptual guide. Multiple cellular mechanisms give rise to phrenic motor facilitation; one mechanism requires spinal serotonin receptor and NADPH oxidase activity whereas another requires spinal adenosine receptor activation. Here, we studied whether these mechanisms contribute to compensatory respiratory plasticity in SOD1G93A rats. Using plethysmography, we assessed ventilation in end-stage SOD1G93A rats after: (1) serotonin depletion with parachlorophenylalanine (PCPA), (2) serotonin (methysergide) and A2A (MSX-3) receptor inhibition, (3) NADPH oxidase inhibition (apocynin), and (4) combined treatments. The ability to increase ventilation was not decreased by individual or combined treatments; thus, these mechanisms do not maintain breathing capacity at end-stage motor neuron disease. Possible mechanisms giving rise to enhanced breathing capacity with combined treatment in end-stage SOD1G93A rats are discussed.
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PMID:Neither serotonin nor adenosine-dependent mechanisms preserve ventilatory capacity in ALS rats. 2468 28