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Extracellular mutant SOD1 induces microglial‐mediated motoneuron injury
Open accessAbstract
Through undefined mechanisms, dominant mutations in (Cu/Zn) superoxide dismutase‐1 (mSOD1) cause the non‐cell‐autonomous death of motoneurons in inherited amyotrophic lateral sclerosis (ALS). Microgliosis at sites of motoneuron injury is a neuropathological hallmark of ALS. Extracellular mutant SOD1 (mSOD1) causes motoneuron injury and triggers microgliosis in spinal cord cultures, but it is unclear whether the injury results from extracellular mSOD1 directly interacting with motoneurons or is mediated through mSOD1‐activated microglia. To dissociate these potential mSOD1‐mediated neurotoxic mechanisms, the effects of extracellular human mSOD1 G93A or mSOD1 G85R were assayed using primary cultures of motoneurons and microglia. The data demonstrate that exogenous mSOD1 G93A did not cause detectable direct killing of motoneurons. In contrast, mSOD1 G93A or mSOD1 G85R did induce the morphological and functional activation of microglia, increasing their release of pro‐inflammatory cytokines and free radicals. Furthermore, only when microglia was co‐cultured with motoneurons did extracellular mSOD1 G93A injure motoneurons. The microglial activation mediated by mSOD1 G93A was attenuated using toll‐like receptors (TLR) 2, TLR4 and CD14 blocking antibodies, or when microglia lacked CD14 expression. These data suggest that extracellular mSOD1 G93A is not directly toxic to motoneurons but requires microglial activation for toxicity, utilizing CD14 and TLR pathways. This link between mSOD1 and innate immunity may offer novel therapeutic targets in ALS. © 2009 Wiley‐Liss, Inc.
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“SR-B2 promotes α-synuclein–microglial interactions64 and senses misfolded mutant or oxidized SOD1 in diseased motor neurons or in the extracellular space, rendering these cells proinflammatory85.”
From Microglia in neurodegeneration (2018) · cites this paper as [85]
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“For example, in primary mouse microglia, SOD1G93A protein caused NLRP3 inflammasome activation and a significant increase in the release of pro-inflammatory factors such as TNF, IL-1β, superoxide, and iNOS.507”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [507]
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“Additionally, pathological proteins of ALS can be secreted into the extracellular matrix, and these pathological proteins are sensed by microglia, causing microglial activation and pro-inflammatory effect that are harmful to co-cultured motor neurons.”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [507]
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Metadata
- Authors
- Zhao, W., Beers, D. R., Henkel, J. S., Zhang, W., Urushitani, M., Julien, J., & Appel, S. H.
- Affiliations
- Houston Methodist (US)
- Shiga University of Medical Science (JP)
- Université Laval (CA)
- Corresponding author
- Appel, Stanley H.
- Venue
- Glia
- Publisher
- Wiley
- Published
- 2009-08-11
- Volume
- 58
- Issue
- 2
- Pages
- 231-243
- ISSN
- 0894-1491 (ISSN-L)
- 1098-1136
- PMC
- PMC2784168
- OpenAlex
- W2066874059
- Cited by
- 288
- References
- 51
- Citations by year
- 2026: 8 · 2025: 16 · 2024: 15 · 2023: 12 · 2022: 13 · 2021: 19 · 2020: 21 · 2019: 13 · 2018: 15 · 2017: 19 · 2016: 18 · 2015: 16 · 2014: 16 · 2013: 23 · 2012: 24
- FWCI
- 13.61
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Glia (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (NS048950, R01NS048950)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Keywords
- amyotrophic lateral sclerosis, SOD1 mutations, microglial activation, non-cell autonomous neurodegeneration, CD14, Toll-like receptors, TLR2, TLR4, inflammatory cytokines, free radicals, innate immunity, SOD1 G93A
- MeSH terms
- Superoxide Dismutase-1, Animals, Cells, Cultured, Extracellular Space, Humans, Mice, Inbred C57BL, Mice, Transgenic, Motor Neurons, Recombinant Proteins, Spinal Cord, Superoxide Dismutase, Signal Transduction, Cell Death, Microglia, Mice, Knockout, Coculture Techniques, Lipopolysaccharide Receptors, Mutation, Missense, Toll-Like Receptor 2, Toll-Like Receptor 4, Mice
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