ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2014
Abnormal intracellular calcium signaling and SNARE-dependent exocytosis contributes to SOD1G93A astrocyte-mediated toxicity in amyotrophic lateral sclerosis.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 60 papers.
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Who cites it
60 citing papers in PubMed, 87 citations in OpenAlex.
- TDP-43 oxidation and PP1 crosstalk at RNA granule-mitochondria contact sites.Nature communications · 2026Article
- Role of dysregulated calcium homeostasis in astrocytes in neurodegenerative disorders.Nature reviews. Neuroscience · 2026Review
- LPS-induced inflammation differentially affects endogenous CaMolecular medicine (Cambridge, Mass.) · 2026Article
- Review
- Preliminary Analysis of Potentially Overlapping Differentially Expressed Proteins in Both the Spinal Cord and Brain of SOD1 G93A Mice.Current protein & peptide science · 2025Article
- Review
- Astrocytes: The Stars in Neurodegeneration?Biomolecules · 2024Review
- The Diverse Roles of Reactive Astrocytes in the Pathogenesis of Amyotrophic Lateral Sclerosis.Brain sciences · 2024Review
- Astrocyte-Neuron Interactions Contributing to Amyotrophic Lateral Sclerosis Progression.Advances in neurobiology · 2024Review
- The Essential Role of Astrocytes in Neurodegeneration and Neuroprotection.CNS & neurological disorders drug targets · 2024Review
- The Key Role of Astrocytes in Amyotrophic Lateral Sclerosis and Their Commitment to Glutamate Excitotoxicity.International journal of molecular sciences · 2023Review
- Regulation of cortical hyperexcitability in amyotrophic lateral sclerosis: focusing on glial mechanisms.Molecular neurodegeneration · 2023Review
- Astrocytes in human central nervous system diseases: a frontier for new therapies.Signal transduction and targeted therapy · 2023Review
- Electrophysiological In Vitro Study of Long-Range Signal Transmission by Astrocytic Networks.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2023Article
- Article
- Astrocytes: Dissecting Their Diverse Roles in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia.Cells · 2023Review
- Astrocyte contribution to dysfunction, risk and progression in neurodegenerative disorders.Nature reviews. Neuroscience · 2023Review
- Why should we care about astrocytes in a motor neuron disease?Frontiers in molecular medicine · 2023Review
- Store-operated calcium entry is reduced in spastin-linked hereditary spastic paraplegia.Brain : a journal of neurology · 2022Article
- SOD1 in ALS: Taking Stock in Pathogenic Mechanisms and the Role of Glial and Muscle Cells.Antioxidants (Basel, Switzerland) · 2022Review
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Authors and funding
11 authors at 4 institutions in 1 country.
Funding
Abstract
Motor neurons are progressively and predominantly degenerated in ALS, which is not only induced by multiple intrinsic pathways but also significantly influenced by the neighboring glial cells. In particular, astrocytes derived from the SOD1 mutant mouse model of ALS or from human familial or sporadic ALS patient brain tissue directly induce motor neuron death in culture; however, the mechanisms of pathological astroglial secretion remain unclear. Here we investigated abnormal calcium homeostasis and altered exocytosis in SOD1G93A astrocytes. We found that purinergic stimulation induces excess calcium release from the ER stores in SOD1G93A astrocytes, which results from the abnormal ER calcium accumulation and is independent of clearance mechanisms. Furthermore, pharmacological studies suggested that store-operated calcium entry (SOCE), a calcium refilling mechanism responsive to ER calcium depletion, is enhanced in SOD1G93A astrocytes. We found that oxidant-induced increased S-glutathionylation and calcium-independent puncta formation of the ER calcium sensor STIM1 underlies the abnormal SOCE response in SOD1G93A astrocytes. Enhanced SOCE contributes to ER calcium overload in SOD1G93A astrocytes and excess calcium release from the ER during ATP stimulation. In addition, ER calcium release induces elevated ATP release from SOD1G93A astrocytes, which can be inhibited by the overexpression of dominant-negative SNARE. Selective inhibition of exocytosis in SOD1G93A astrocytes significantly prevents astrocyte-mediated toxicity to motor neurons and delays disease onset in SOD1G93A mice. Our results characterize a novel mechanism responsible for calcium dysregulation in SOD1G93A astrocytes and provide the first in vivo evidence that astrocyte exocytosis contributes to the pathogenesis of ALS.
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Registered trials
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