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The Journal of Neuroscience, December 10, 2008, 28(50):13574-13581; doi:10.1523/JNEUROSCI.4099-08.2008

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Neurobiology of Disease
Nrf2 Activation in Astrocytes Protects against Neurodegeneration in Mouse Models of Familial Amyotrophic Lateral Sclerosis

Marcelo R. Vargas,¹ Delinda A. Johnson,¹ Daniel W. Sirkis,¹ Albee Messing,^2,3 and Jeffrey A. Johnson^1,2,4,5

¹Division of Pharmaceutical Sciences, ²Waisman Center, ³Department of Comparative Biosciences, ⁴Molecular and Environmental Toxicology Center, and ⁵Center for Neuroscience, University of Wisconsin–Madison, Madison, Wisconsin 53705-2222

Correspondence should be addressed to Dr. Jeffrey A. Johnson, School of Pharmacy, 6125 Rennebohm Hall, University of Wisconsin–Madison, Madison, WI 53705-2222. Email: jajohnson{at}pharmacy.wisc.edu

Activation of the transcription factor Nrf2 in astrocytes coordinates the upregulation of antioxidant defenses and confers protection to neighboring neurons. Dominant mutations in Cu/Zn-superoxide dismutase (SOD1) cause familial forms of amyotrophic lateral sclerosis (ALS), a fatal disorder characterized by the progressive loss of motor neurons. Non-neuronal cells, including astrocytes, shape motor neuron survival in ALS and are a potential target to prevent motor neuron degeneration. The protective effect of Nrf2 activation in astrocytes has never been examined in a chronic model of neurodegeneration. We generated transgenic mice over-expressing Nrf2 selectively in astrocytes using the glial fibrillary acidic protein (GFAP) promoter. The toxicity of astrocytes expressing ALS-linked mutant hSOD1 to cocultured motor neurons was reversed by Nrf2 over-expression. Motor neuron protection depended on increased glutathione secretion from astrocytes. This protective effect was also observed by crossing the GFAP-Nrf2 mice with two ALS-mouse models. Over-expression of Nrf2 in astrocytes significantly delayed onset and extended survival. These findings demonstrate that Nrf2 activation in astrocytes is a viable therapeutic target to prevent chronic neurodegeneration.

Key words: Nrf2; astrocytes; glutathione; motor neurons; neuronal death; neuroprotection

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Received Aug. 27, 2008; revised Oct. 8, 2008; accepted Nov. 5, 2008.

Correspondence should be addressed to Dr. Jeffrey A. Johnson, School of Pharmacy, 6125 Rennebohm Hall, University of Wisconsin–Madison, Madison, WI 53705-2222. Email: jajohnson{at}pharmacy.wisc.edu

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