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

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 ( ⅐ 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 ⅐ 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.

Mitochondrial Dysfunction in SOD1G93A-Bearing Astrocytes Promotes Motor Neuron Degeneration: Prevention by Mitochondrial-Targeted Antioxidants

“…formation (Pehar et al, 2007). As a first step toward mitochondria-specific therapies, the Murphy and Kalyanaraman laboratories have developed bioactive molecules delivered to mitochondria by covalent attachment to the triphenylphosphonium cation through an alkyl chain (Kelso et al, 2001;Dhanasekaran et al, 2005).…”

Dynamic Meta-Analysis as a Therapeutic Prediction Tool for Amyotrophic Lateral Sclerosis

“…Free radicals initiate reactions that damage DNA (Pehar, Vargas et al 2007). Necro-apoptosis: encompasses the measures of cell death, including the signaling cascades, their constituents, and machinery, which promote cell death.…”

“…Kruman,1999;Kruman, 1999;Ellis, 2003) Energetics L - (Liu, 1996;Liu, 1999;Mattson, 1999;Liu, 2002;Cassina, 2005) Free Radicals M - (Liu 1996;Liu. 1999;Cookson, 2002;Cassina, Pehar 2005;Pehar 2007) www.intechopen.com …”

Reactive Nitrogen Species in Motor Neuron Apoptosis

“…Even when the source of superoxide for the formation of peroxynitrite in vivo and in cultured motor neurons remains unknown, evidence from other neuronal types suggest that the induction and activation of NADPH oxidase might be responsible for the production of superoxide that makes nitric oxide toxic to motor neurons (Noh and Koh 2000;Tammariello, Quinn, and Estus 2000). In motor neurons, activation of the p75 neurotrophic receptor results in apoptosis in different conditions (Ricart et al 2006;Pehar et al 2004;Pehar et al 2007;Wiese et al 1999). At least in part this toxicity is mediated by induction of superoxide production by mitochondria (Pehar et al 2007).…”

“…In motor neurons, activation of the p75 neurotrophic receptor results in apoptosis in different conditions (Ricart et al 2006;Pehar et al 2004;Pehar et al 2007;Wiese et al 1999). At least in part this toxicity is mediated by induction of superoxide production by mitochondria (Pehar et al 2007). In summary, inhibition of nitric oxide production blocks motor neuron death induced by ventral root avulsion, and deletion of SOD increases the sensitivity of motor neurons to the same noxious stimulus.…”