Mitochondrial Superoxide Production and Nuclear Factor Erythroid 2-Related Factor 2 Activation in p75 Neurotrophin Receptor-Induced Motor Neuron Apoptosis

• DOI: 10.1523/jneurosci.0823-07.2007
• Publication Date: 2007-07-18T17:28:28Z
• Authors: Mariana Pehar; Marcelo R. Vargas; Kristine M. Robinson; Patricia Cassina; Pablo J. Díaz-Ama...; Tory M. Hagen; Rafael Radi; Luis Barbeito; Joseph S. Beckman
• Keywords: Motor Neurons; 0303 health sciences; NF-E2-Related Factor 2; Cytochromes c; Apoptosis; Embryo, Mammalian; Receptor, Nerve Growth Factor; Mitochondria; Oligodeoxyribonucleotides, Antisense; Rats; Animals, Genetically Modified; Enzyme Activation; Rats, Sprague-Dawley; 03 medical and health sciences; Gene Expression Regulation; Nerve Growth Factor; Animals; Nitric Oxide Donors; Enzyme Inhibitors; Reactive Oxygen Species; Cells, Cultured; Nitroso Compounds

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 are not vulnerable to NGF unless they exposed an exogenous flux of nitric oxide ( • NO). In present study, we show that -mediated involved neutral sphingomyelinase activation, increased mitochondrial superoxide production, and cytochrome c release cytosol. The mitochondria-targeted antioxidants mitoQ mitoCP prevented neuronal loss, further evidencing role mitochondria NGF-induced apoptosis. overexpressing amyotrophic lateral sclerosis (ALS)-linked dismutase 1 G93A (SOD1 mutation, induced even absence external source NO. susceptibility SOD1 was associated decreased nuclear erythroid 2-related 2 (Nrf2) expression downregulation enzymes glutathione biosynthesis. agreement, depletion nontransgenic reproduced effect expression, increasing their sensitivity NGF. contrast, rising antioxidant defenses Nrf2 activation Together, our data indicate neuron involves ceramide-dependent production. This apoptotic pathway is facilitated ALS-linked mutations critically modulated activity.