Astrocytes from familial and sporadic ALS patients are toxic to motor neurons
Open accessAbstract
Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease, with astrocytes implicated as contributing substantially to motor neuron death in familial (F)ALS. However, the proposed role of astrocytes in the pathology of ALS derives in part from rodent models of FALS based upon dominant mutations within the superoxide dismutase 1 (SOD1) gene, which account for <2% of all ALS cases. Their role in sporadic (S)ALS, which affects >90% of ALS patients, remains to be established. Using astrocytes generated from postmortem tissue from both FALS and SALS patients, we show that astrocytes derived from both patient groups are similarly toxic to motor neurons. We also demonstrate that SOD1 is a viable target for SALS, as its knockdown significantly attenuates astrocyte-mediated toxicity toward motor neurons. Our data highlight astrocytes as a non-cell autonomous component in SALS and provide an in vitro model system to investigate common disease mechanisms and evaluate potential therapies for SALS and FALS.
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Conditioned media from SOD1-G93A astrocytes is toxic to motor neurons.
“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 [25]
The paper reports that conditioned media from patient-derived familial and sporadic ALS astrocytes accelerated motor-neuron death (results describing Fig. 2e–f; page unavailable). It also reports motor-neuron toxicity when SOD1-G93A was overexpressed in astrocytes, but that result came from co-culture experiments, not a reported test of conditioned media from those astrocytes. (LLM, conf=0.86)
Experimental — accuracy not yet measuredIn mutant SOD1 transgenic mice, continued unabridged neuroinflammation enhances neurodegeneration and accelerates disease progression.
“however, with time the continued and unabridged neuroinflammation only enhances neurodegeneration and accelerates disease progression [434–436].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [434]
In pre-symptomatic mutant SOD1 transgenic mice, activated microglia initially display neuroprotective properties that slow disease progression.
“In pre-symptomatic mutant SOD1 transgenic mice, activated microglia initially display neuroprotective properties that slow disease progression;”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [434]
Astrocytes seem to secrete toxic factor(s) that are detrimental to motor neuron health.
“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 [25]
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- Authors
- Haidet-Phillips, A. M., Hester, M. E., Miranda, C. J., Meyer, K., Braun, L., Frakes, A., Song, S., Likhite, S., Murtha, M. J., Foust, K. D., Rao, M., Eagle, A., Kammesheidt, A., Christensen, A., Mendell, J. R., Burghes, A. H. M., & Kaspar, B. K.
- Affiliations
- Nationwide Children's Hospital (US)
- Ambry Genetics (United States) (US)
- The Ohio State University (US)
- Corresponding author
- Kaspar, Brian K
- ORCID
- Venue
- Nature Biotechnology
- Published
- 2011-08-10
- Volume
- 29
- Issue
- 9
- Pages
- 824-828
- ISSN
- 0733-222X (ISSN-L)
- 1087-0156
- 1546-1696
- PMC
- PMC3170425
- OpenAlex
- W2059355164
- Cited by
- 782
- References
- 30
- Citations by year
- 2026: 21 · 2025: 29 · 2024: 43 · 2023: 38 · 2022: 54 · 2021: 46 · 2020: 68 · 2019: 59 · 2018: 55 · 2017: 58 · 2016: 66 · 2015: 59 · 2014: 70 · 2013: 59 · 2012: 50
- FWCI
- 37.69
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Biotechnology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (RC2NS069476, R01 NS644912-1A1, RC2 NS69476-01, R01NS064492, T32NS077984, F31NS058224)
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Keywords
- amyotrophic lateral sclerosis, astrocytes, motor neuron toxicity, sporadic ALS, familial ALS, SOD1, disease mechanisms
- MeSH terms
- Superoxide Dismutase-1, Amyotrophic Lateral Sclerosis, Animals, Astrocytes, Cell Differentiation, Cell Line, Disease Models, Animal, Gene Expression Regulation, Humans, Immunohistochemistry, Motor Neurons, Mutation, Superoxide Dismutase, Signal Transduction, Biomarkers, Sequence Analysis, DNA, Coculture Techniques, Mice, Embryonic Stem Cells, Mesenchymal Stem Cells
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