ArticleJournal of neurophysiology2013
Mutant SOD1-expressing astrocytes release toxic factors that trigger motoneuron death by inducing hyperexcitability.
Article in Journal of neurophysiology, 2013. 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, 113 citations in OpenAlex.
- Effects of mexiletine on hyperexcitability in sporadic amyotrophic lateral sclerosis: Preliminary findings from a small phase II randomized controlled trial.Muscle & nerve · 2021Trial
- A randomized trial of mexiletine in ALS: Safety and effects on muscle cramps and progression.Neurology · 2016Trial
- Flecainide in Amyotrophic Lateral Sclerosis as a Neuroprotective Strategy (FANS): A Randomized Placebo-Controlled Trial.EBioMedicine · 2015Trial
- Review
- Cutting-edge treatments in amyotrophic lateral sclerosis: the role of molecular pathogenesis in targeted therapies.Stem cell research & therapy · 2025Review
- Novel Dual Mechanism GRT-X Agonist Acting on Kv7 Potassium Channel/Translocator Protein Receptor Prevents Motoneuron Degeneration Following Exposure to Mouse and Human Amyotrophic Lateral Sclerosis/Frontotemporal Dementia Astrocyte-Conditioned Media.ACS chemical neuroscience · 2025Article
- Boldine as a neuroprotective agent against motor neuron degeneration in models of amyotrophic lateral sclerosis.Frontiers in cellular neuroscience · 2025Article
- Skeletal myotubes expressing ALS mutant SOD1 induce pathogenic changes, impair mitochondrial axonal transport, and trigger motoneuron death.Molecular medicine (Cambridge, Mass.) · 2024Article
- Astrocytes: The Stars in Neurodegeneration?Biomolecules · 2024Review
- Inhibition ofBrain communications · 2024Article
- Astrocyte-Neuron Interactions Contributing to Amyotrophic Lateral Sclerosis Progression.Advances in neurobiology · 2024Review
- Excitatory to inhibitory synaptic ratios are unchanged at presymptomatic stages in multiple models of ALS.PloS one · 2024Article
- Therapeutic targeting of ALS pathways: Refocusing an incomplete picture.Annals of clinical and translational neurology · 2023Review
- Regulation of cortical hyperexcitability in amyotrophic lateral sclerosis: focusing on glial mechanisms.Molecular neurodegeneration · 2023Review
- Astrocytes: Dissecting Their Diverse Roles in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia.Cells · 2023Review
- Protein kinase B (AKT) upregulation and Thy-1-αJournal of neuroinflammation · 2023Article
- Why should we care about astrocytes in a motor neuron disease?Frontiers in molecular medicine · 2023Review
- Mature iPSC-derived astrocytes of an ALS/FTD patient carrying the TDP43Frontiers in cell and developmental biology · 2023Article
- Astrocytic modulation of neuronal signalling.Frontiers in network physiology · 2023Review
- Article
Corrections and comments
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Authors and funding
10 authors at 5 institutions in 3 countries.
Funding
Abstract
Amyotrophic lateral sclerosis (ALS) is a devastating paralytic disorder caused by dysfunction and degeneration of motoneurons starting in adulthood. Recent studies using cell or animal models document that astrocytes expressing disease-causing mutations of human superoxide dismutase 1 (hSOD1) contribute to the pathogenesis of ALS by releasing a neurotoxic factor(s). Neither the mechanism by which this neurotoxic factor induces motoneuron death nor its cellular site of action has been elucidated. Here we show that acute exposure of primary wild-type spinal cord cultures to conditioned medium derived from astrocytes expressing mutant SOD1 (ACM-hSOD1(G93A)) increases persistent sodium inward currents (PC(Na)), repetitive firing, and intracellular calcium transients, leading to specific motoneuron death days later. In contrast to TTX, which paradoxically increased twofold the amplitude of calcium transients and killed motoneurons, reduction of hyperexcitability by other specific (mexiletine) and nonspecific (spermidine and riluzole) blockers of voltage-sensitive sodium (Na(v)) channels restored basal calcium transients and prevented motoneuron death induced by ACM-hSOD1(G93A). These findings suggest that riluzole, the only FDA-approved drug with known benefits for ALS patients, acts by inhibiting hyperexcitability. Together, our data document that a critical element mediating the non-cell-autonomous toxicity of ACM-hSOD1(G93A) on motoneurons is increased excitability, an observation with direct implications for therapy of ALS.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.