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

• Published in: The Journal of neuroscience Vol. 28; no. 50; pp. 13574 - 13581
• Main Authors: Vargas, Marcelo R, Johnson, Delinda A, Sirkis, Daniel W, Messing, Albee, Johnson, Jeffrey A
• Format: Journal Article
• Language: English
• Published: United States Soc Neuroscience 10.12.2008; Society for Neuroscience
• Subjects: Amyotrophic Lateral Sclerosis - metabolism; Amyotrophic Lateral Sclerosis - pathology; Animals; Astrocytes - metabolism; Blotting, Western; Coculture Techniques; Disease Models, Animal; Fluorescent Antibody Technique; Glutathione - metabolism; Humans; Immunohistochemistry; Mice; Mice, Transgenic; Motor Neurons - pathology; Muscle, Skeletal - innervation; Nerve Degeneration - metabolism; Nerve Degeneration - pathology; Nerve Degeneration - prevention & control; NF-E2-Related Factor 2 - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Spinal Cord - pathology; Superoxide Dismutase - genetics; Superoxide Dismutase - metabolism; Superoxide Dismutase-1
• ISSN: 0270-6474; 1529-2401; 1529-2401
• DOI: 10.1523/JNEUROSCI.4099-08.2008

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.