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The Journal of Neuroscience, August 16, 2006, 26(33):8512-8516; doi:10.1523/JNEUROSCI.0728-06.2006

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Brief Communications
Arginase 1 Regulation of Nitric Oxide Production Is Key to Survival of Trophic Factor-Deprived Motor Neurons

Alvaro G. Estévez,^1,2 Mary Anne Sahawneh,^1,2 Philipp S. Lange,^1,2 Narae Bae,^1,2 Mariela Egea,^1,2 and Rajiv R. Ratan^1,2

¹Burke Medical Research Institute, White Plains, New York 10605, and ²Department of Neurology and Neurosciences, Weill Medical School of Cornell University, New York, New York 10021

Correspondence should be addressed to Dr. Alvaro G. Estévez, Burke Research Institute, 785 Mamaroneck Avenue, White Plains, NY 10605. Email: age2002{at}med.cornell.edu

When deprived of trophic factors, the majority of cultured motor neurons undergo nitric oxide-dependent apoptosis. However, for reasons that have remained unclear, 30–50% of the motor neurons survive for several days without trophic factors. Here we hypothesize that the resistance of this motor neuron subpopulation to trophic factor deprivation can be attributed to diminished nitric oxide production resulting from the activity of the arginine-degrading enzyme arginase. When incubated with nor-N^G-hydroxy-nor-L-arginine (NOHA), the normally resistant trophic factor-deprived motor neurons showed a drop in survival rates, whereas trophic factor-treated neurons did not. NOHA-induced motor neuron death was inhibited by blocking nitric oxide synthesis and the scavenging of superoxide and peroxynitrite, suggesting that peroxynitrite mediates NOHA toxicity. When we transfected arginase 1 into motor neurons to see whether it alone could abrogate trophic factor deprivation-induced death, we found that its forced expression did indeed do so. The protection afforded by arginase 1 expression is reversed when cells are incubated with NOHA or with low concentrations of nitric oxide. These results reveal that arginase acts as a central regulator of trophic factor-deprived motor neuron survival by suppressing nitric oxide production and the consequent peroxynitrite toxicity. They also suggest that the resistance of motor neuron subpopulations to trophic factor deprivation may result from increased arginase activity.

Key words: nitric oxide; motor neurons; arginase; peroxynitrite; apoptosis; trophic factor deprivation

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Received Feb. 17, 2006; revised June 15, 2006; accepted June 24, 2006.

Correspondence should be addressed to Dr. Alvaro G. Estévez, Burke Research Institute, 785 Mamaroneck Avenue, White Plains, NY 10605. Email: age2002{at}med.cornell.edu

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