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The Journal of Neuroscience, July 18, 2007, 27(29):7777-7785; doi:10.1523/JNEUROSCI.0823-07.2007

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

Mariana Pehar,¹ Marcelo R. Vargas,¹ Kristine M. Robinson,⁴ Patricia Cassina,² Pablo J. Díaz-Amarilla,¹ Tory M. Hagen,⁴ Rafael Radi,³ Luis Barbeito,¹ and Joseph S. Beckman⁴

¹Departamento de Neurobiología Celular y Molecular, Instituto de Investigaciones Biológicas Clemente Estable, Montevideo 11600, Uruguay, ²Departamento de Histología and ³Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, Montevideo 11800, Uruguay, and ⁴Department of Biochemistry and Biophysics, Oregon State University, Linus Pauling Institute, Corvallis, Oregon 97331

Correspondence should be addressed to Dr. Joseph S. Beckman, Linus Pauling Institute, Oregon State University, 571 Weniger Hall, Corvallis, OR 97331-6512. Email: joe.beckman{at}oregonstate.edu

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.

Key words: amyotrophic lateral sclerosis; mitochondria; motor neurons; nerve growth factor; Nrf2; p75^NTR; superoxide

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Received Feb. 22, 2007; revised June 3, 2007; accepted June 5, 2007.

Correspondence should be addressed to Dr. Joseph S. Beckman, Linus Pauling Institute, Oregon State University, 571 Weniger Hall, Corvallis, OR 97331-6512. Email: joe.beckman{at}oregonstate.edu

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