Mitochondrial superoxide production and nuclear factor erythroid 2-related factor 2 activation in p75 neurotrophin receptor-induced motor neuron apoptosis.

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  • Additional Information
    • Source:
      Publisher: Society for Neuroscience Country of Publication: United States NLM ID: 8102140 Publication Model: Print Cited Medium: Internet ISSN: 1529-2401 (Electronic) Linking ISSN: 02706474 NLM ISO Abbreviation: J Neurosci Subsets: MEDLINE
    • Publication Information:
      Publication: Washington, DC : Society for Neuroscience
      Original Publication: [Baltimore, Md.] : The Society, c1981-
    • Subject Terms:
      Apoptosis/*physiology ; Mitochondria/*metabolism ; Motor Neurons/*physiology ; NF-E2-Related Factor 2/*metabolism ; Receptor, Nerve Growth Factor/*metabolism ; Spinal Cord/*cytology; Animals ; Animals, Genetically Modified ; Apoptosis/drug effects ; Cells, Cultured ; Cytochromes c/metabolism ; Embryo, Mammalian ; Enzyme Activation/drug effects ; Enzyme Inhibitors/pharmacology ; Gene Expression Regulation/drug effects ; Gene Expression Regulation/physiology ; Mitochondria/drug effects ; Motor Neurons/drug effects ; Nerve Growth Factor/pharmacology ; Nitric Oxide Donors/pharmacology ; Nitroso Compounds/pharmacology ; Oligodeoxyribonucleotides, Antisense/pharmacology ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Sphingomyelin Phosphodiesterase/metabolism ; Superoxide Dismutase/genetics ; Superoxide Dismutase/pharmacology
    • Abstract:
      Nerve growth factor (NGF) can induce apoptosis by signaling through the p75 neurotrophin receptor (p75(NTR)) in several nerve cell populations. Cultured embryonic motor neurons expressing p75(NTR) are not vulnerable to NGF unless they are exposed to an exogenous flux of nitric oxide (*NO). In the present study, we show that p75(NTR)-mediated apoptosis in motor neurons involved neutral sphingomyelinase activation, increased mitochondrial superoxide production, and cytochrome c release to the cytosol. The mitochondria-targeted antioxidants mitoQ and mitoCP prevented neuronal loss, further evidencing the role of mitochondria in NGF-induced apoptosis. In motor neurons overexpressing the amyotrophic lateral sclerosis (ALS)-linked superoxide dismutase 1(G93A) (SOD1(G93A)) mutation, NGF induced apoptosis even in the absence of an external source of *NO. The increased susceptibility of SOD1(G93A) motor neurons to NGF was associated to decreased nuclear factor erythroid 2-related factor 2 (Nrf2) expression and downregulation of the enzymes involved in glutathione biosynthesis. In agreement, depletion of glutathione in nontransgenic motor neurons reproduced the effect of SOD1(G93A) expression, increasing their sensitivity to NGF. In contrast, rising antioxidant defenses by Nrf2 activation prevented NGF-induced apoptosis. Together, our data indicate that p75(NTR)-mediated motor neuron apoptosis involves ceramide-dependent increased mitochondrial superoxide production. This apoptotic pathway is facilitated by the expression of ALS-linked SOD1 mutations and critically modulated by Nrf2 activity.
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    • Grant Information:
      P30 ES000210 United States ES NIEHS NIH HHS; R03TW006482 United States TW FIC NIH HHS; P01 ES000040 United States ES NIEHS NIH HHS; AT02034 United States AT NCCIH NIH HHS; R03 TW006482 United States TW FIC NIH HHS; P01 AT002034 United States AT NCCIH NIH HHS; ES00040 United States ES NIEHS NIH HHS; ES00210 United States ES NIEHS NIH HHS
    • Accession Number:
      0 (Enzyme Inhibitors)
      0 (NF-E2-Related Factor 2)
      0 (Nfe2l2 protein, rat)
      0 (Nitric Oxide Donors)
      0 (Nitroso Compounds)
      0 (Oligodeoxyribonucleotides, Antisense)
      0 (Reactive Oxygen Species)
      0 (Receptor, Nerve Growth Factor)
      146724-94-9 (2,2'-(hydroxynitrosohydrazono)bis-ethanamine)
      9007-43-6 (Cytochromes c)
      9061-61-4 (Nerve Growth Factor)
      EC 1.15.1.1 (SOD1 G93A protein)
      EC 1.15.1.1 (Superoxide Dismutase)
      EC 3.1.4.12 (Sphingomyelin Phosphodiesterase)
    • Publication Date:
      Date Created: 20070720 Date Completed: 20070823 Latest Revision: 20230131
    • Publication Date:
      20240829
    • Accession Number:
      PMC6672870
    • Accession Number:
      10.1523/JNEUROSCI.0823-07.2007
    • Accession Number:
      17634371