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ALS-Linked SOD1 Mutant G85R Mediates Damage to Astrocytes and Promotes Rapidly Progressive Disease with SOD1-Containing Inclusions
Open accessAbstract
High levels of familial Amyotrophic Lateral Sclerosis (ALS)-linked SOD1 mutants G93A and G37R were previously shown to mediate disease in mice through an acquired toxic property. We report here that even low levels of another mutant, G85R, cause motor neuron disease characterized by an extremely rapid clinical progression, without changes in SOD1 activity. Initial indicators of disease are astrocytic inclusions that stain intensely with SOD1 antibodies and ubiquitin and SOD1-containing aggregates in motor neurons, features common with some cases of SOD1 mutant-mediated ALS. Astrocytic inclusions escalate markedly as disease progresses, concomitant with a decrease in the glial glutamate transporter (GLT-1). Thus, the G85R SOD1 mutant mediates direct damage to astrocytes, which may promote the nearly synchronous degeneration of motor neurons.
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“implying that astrocytes are both necessary and sufficient for neurodegeneration in this ALS model.”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [414]
In the citing paper
“Selective clearance of SOD1-positive inclusions from astrocytes is sufficient to slow disease progression [414]”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [414]
In the citing paper
“In transgenic mice overexpressing mutant SOD1 associated with ALS, astrocytes display more SOD1-positive inclusions than do neurons, and at an earlier stage [414].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [414]
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Ca2+, mitochondria and selective motoneuron vulnerability: implications for ALS
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Metal ions as modulators of protein conformation and misfolding in neurodegeneration
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Role of mutant SOD1 disulfide oxidation and aggregation in the pathogenesis of familial ALS
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In vivo genome editing improves motor function and extends survival in a mouse model of ALS
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“Although the mechanism behind SOD1 toxicity is not completely understood (4), transgenic animals that express mutant forms of the gene develop a progressive neurodegenerative disease that emulates the hallmarks ofALS (5, 6), including motor neuron degeneration, muscle wasting, and paralysis.”
Background
Metadata
- Authors
- Bruijn, L. I., Becher, M. W., Lee, M. K., Anderson, K. L., Jenkins, N. A., Copeland, N. G., Sisodia, S. S., Rothstein, J. D., Borchelt, D. R., Price, D. L., & Cleveland, D. W.
- Affiliations
- University of California San Diego (US)
- Johns Hopkins University (US)
- National Cancer Institute (US)
- Corresponding author
- Cleveland, D.W.
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 1997-02
- Volume
- 18
- Issue
- 2
- Pages
- 327-338
- ISSN
- 0896-6273 (ISSN-L)
- OpenAlex
- W2012851706
- Cited by
- 1,341
- References
- 39
- Citations by year
- 2026: 10 · 2025: 22 · 2024: 23 · 2023: 30 · 2022: 41 · 2021: 40 · 2020: 36 · 2019: 35 · 2018: 36 · 2017: 40 · 2016: 47 · 2015: 44 · 2014: 52 · 2013: 52 · 2012: 64
- FWCI
- 37.57
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Neuron (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Muscular Dystrophy Association
- National Institute on Aging (P50AG005146, AG 05146)
- National Institute of Neurological Disorders and Stroke (NS10580, NS 27036)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Keywords
- amyotrophic lateral sclerosis, SOD1 G93A, astrocyte damage, motor neuron degeneration, disease progression, glutamate transporter GLT-1, ubiquitin, familial ALS
- MeSH terms
- Amyotrophic Lateral Sclerosis, Animals, Astrocytes, Axons, Disease Models, Animal, Genes, Dominant, Humans, Mice, Transgenic, Microscopy, Electron, Nerve Degeneration, Neurons, Spinal Cord, Superoxide Dismutase, Ubiquitins, Point Mutation, ATP-Binding Cassette Transporters, Amino Acid Transport System X-AG, Mice
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