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Astrocytes expressing ALS-linked mutated SOD1 release factors selectively toxic to motor neurons
Open accessAbstract
Mutations in superoxide dismutase-1 (SOD1) cause a form of the fatal paralytic disorder amyotrophic lateral sclerosis (ALS), presumably by a combination of cell-autonomous and non-cell-autonomous processes. Here, we show that expression of mutated human SOD1 in primary mouse spinal motor neurons does not provoke motor neuron degeneration. Conversely, rodent astrocytes expressing mutated SOD1 kill spinal primary and embryonic mouse stem cell-derived motor neurons. This is triggered by soluble toxic factor(s) through a Bax-dependent mechanism. However, mutant astrocytes do not cause the death of spinal GABAergic or dorsal root ganglion neurons or of embryonic stem cell-derived interneurons. In contrast to astrocytes, fibroblasts, microglia, cortical neurons and myocytes expressing mutated SOD1 do not cause overt neurotoxicity. These findings indicate that astrocytes may play a role in the specific degeneration of spinal motor neurons in ALS. Identification of the astrocyte-derived soluble factor(s) may have far-reaching implications for ALS from both a pathogenic and therapeutic standpoint.
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“Accumulating evidence has demonstrated that glia are involved in a variety of neurological diseases, including schizophrenia, autism spectrum disorders, epilepsy, Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, and stroke (Matute et al., 2005;Tian et al., 2005;Nagai et al., 2007;Chen et al., 2009;Li et al., 2011;Lioy et al., 2011;Molofsky et al., 2012;Z”
From An RNA-Sequencing Transcriptome and Splicing Database of Glia, Neurons, and Vascular Cells of the Cerebral Cortex (2014) · cites this paper as Nagai et al., 2007
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“Moreover, astrocytes seem to secrete toxic factor(s) that are detrimental to motor neuron health [23–26].”
From Distinct repertoires of microRNAs present in mouse astrocytes compared to astrocyte-secreted exosomes (2017) · cites this paper as [23]
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“Consistent with previous studies [23–26], we validated that the conditioned media from these cultures is toxic to motor neurons.”
From Distinct repertoires of microRNAs present in mouse astrocytes compared to astrocyte-secreted exosomes (2017) · cites this paper as [23]
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“Previous evidence suggested the toxic activity of reactive astrocytes is mediated by a secreted protein5,6”
From Neurotoxic reactive astrocytes induce cell death via saturated lipids (2021) · cites this paper as [5]
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Metadata
- Authors
- Nagai, M., Re, D. B., Nagata, T., Chalazonitis, A., Jessell, T. M., Wichterle, H., & Przedborski, S.
- Affiliations
- Columbia University (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Przedborski, Serge
- Venue
- Nature Neuroscience
- Published
- 2007-04-15
- Volume
- 10
- Issue
- 5
- Pages
- 615-622
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC3799799
- OpenAlex
- W2107660300
- Cited by
- 1,220
- References
- 39
- Citations by year
- 2026: 22 · 2025: 31 · 2024: 59 · 2023: 52 · 2022: 50 · 2021: 52 · 2020: 65 · 2019: 53 · 2018: 58 · 2017: 72 · 2016: 53 · 2015: 64 · 2014: 81 · 2013: 84 · 2012: 89
- FWCI
- 57.88
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Muscular Dystrophy Association
- National Institutes of Health
- National Institute on Aging (R01AG021617, AG21617)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK58056, R01DK058056)
- National Institute of Neurological Disorders and Stroke (NS-11766, P01NS011766, R01NS042269, P50NS038370, NS 42269, NS38370)
- National Institute of Environmental Health Sciences (R21ES013177, ES013177)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Keywords
- amyotrophic lateral sclerosis, SOD1 mutations, astrocytes, motor neuron degeneration, non-cell autonomous neurodegeneration, spinal motoneurons
- MeSH terms
- Amyotrophic Lateral Sclerosis, Animals, Astrocytes, Cell Survival, Cells, Cultured, Disease Models, Animal, Dose-Response Relationship, Drug, Embryo, Mammalian, Enzyme Inhibitors, Ganglia, Spinal, Humans, Mice, Transgenic, Motor Neurons, Mutation, Nerve Tissue Proteins, Superoxide Dismutase, Culture Media, Conditioned, In Situ Nick-End Labeling, Green Fluorescent Proteins, Mice, Embryonic Stem Cells
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