Nrf2 activation in astrocytes protects against neurodegeneration in mouse models of familial amyotrophic lateral sclerosis.
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.
Vargas
Marcelo R
MR
Division of Pharmaceutical Sciences, University of Wisconsin-Madison, Madison, Wisconsin 53705-2222, USA.
Johnson
Delinda A
DA
Sirkis
Daniel W
DW
Messing
Albee
A
Johnson
Jeffrey A
JA
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
D051267:NF-E2-Related Factor 2; C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D005978:Glutathione