Nrf2 Activation in Astrocytes Protects against Neurodegeneration in Mouse Models of Familial Amyotrophic Lateral Sclerosis
Open accessAbstract
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.
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Nrf2 activation in astrocytes confers protection against neurodegeneration in mouse models of ALS.
“For example, Nrf2 activation in astrocytes confers protection against neurodegeneration in mouse models of ALS [121]”
From Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease (2022) · cites this paper as [121]
Limited overexpression of NRF2 in astrocytes mitigated neurodegeneration in SOD1G93A and SOD1H46R/H48Q mice.
“limited overexpression of NRF2 in astrocytes mitigated neurodegeneration in SOD1G93A and SOD1H46R/H48Q mice [340].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [340]
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“with the G93A [214,215,335–338], G86R [335,339], or H46R/ H48Q [340] mutations (also reviewed elsewhere [341–344]).”
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- Authors
- Vargas, M. R., Johnson, D. A., Sirkis, D. W., Messing, A., & Johnson, J. A.
- Affiliations
- University of Wisconsin–Madison (US)
- University of Wisconsin System (US)
- Corresponding author
- Johnson, Jeffrey A.
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2008-12-10
- Volume
- 28
- Issue
- 50
- Pages
- 13574-13581
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC2866507
- OpenAlex
- W2009517899
- Cited by
- 479
- References
- 42
- Citations by year
- 2026: 20 · 2025: 18 · 2024: 24 · 2023: 26 · 2022: 21 · 2021: 23 · 2020: 29 · 2019: 24 · 2018: 23 · 2017: 23 · 2016: 24 · 2015: 33 · 2014: 33 · 2013: 30 · 2012: 41
- FWCI
- 18.02
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- ALS Association
- Johns Hopkins University
- National Institute of Neurological Disorders and Stroke (R01NS060120)
- National Institute of Environmental Health Sciences (ES10042, R01ES010042, ES08089, R01ES008089, R29ES008089)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P30HD003352)
- Robert Packard Center for ALS Research, Johns Hopkins University
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Keywords
- Nrf2, astrocytes, familial ALS, SOD1 mutations, motor neuron protection, neurodegeneration, antioxidant defense, GFAP promoter, astrocyte-neuron co-culture, therapeutic target
- MeSH terms
- Superoxide Dismutase-1, Amyotrophic Lateral Sclerosis, Animals, Astrocytes, Disease Models, Animal, Fluorescent Antibody Technique, Glutathione, Humans, Immunohistochemistry, Mice, Transgenic, Motor Neurons, Nerve Degeneration, Spinal Cord, Superoxide Dismutase, Blotting, Western, Muscle, Skeletal, Coculture Techniques, Reverse Transcriptase Polymerase Chain Reaction, NF-E2-Related Factor 2, Mice
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