title: Nrf2 activation in astrocytes protects against neurodegeneration in mouse models of familial amyotrophic lateral sclerosis.
abstract: 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.
authors.affiliation: Division of Pharmaceutical Sciences, University of Wisconsin-Madison, Madison, Wisconsin 53705-2222, USA.
authors.forename: Marcelo R
authors.initials: MR
authors.lastname: Vargas
authors.forename: Delinda A
authors.initials: DA
authors.lastname: Johnson
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Sirkis
authors.forename: Albee
authors.initials: A
authors.lastname: Messing
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Johnson
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D015153:Blotting, Western; D018920:Coculture Techniques; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000473:pathology*; D018482:Muscle, Skeletal / Q000294:innervation; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013116:Spinal Cord / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1
chemical_list: D051267:NF-E2-Related Factor 2; C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D005978:Glutathione