ArticleProceedings of the National Academy of Sciences of the United States of America2022
Cx43 hemichannels contribute to astrocyte-mediated toxicity in sporadic and familial ALS.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers, 1 of them a synthesis that pooled it.
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Who cites it
44 citing papers in PubMed, 1 synthesis or guideline pooled it, 63 citations in OpenAlex.
- The Dual Role of Connexins in Stroke, Neurotrauma, Neurodegenerative and Psychiatric Disorders: A Global Systematic Review.Molecules (Basel, Switzerland) · 2026Pooled it
- Adenosine Deaminase-Mediated Purine Dysfunction Leads to DNA Repair Inhibition and Senescence in Sporadic Amyotrophic Lateral Sclerosis.International journal of molecular sciences · 2026Article
- Astrocytes in Neurodegeneration: Spatial States, Crosstalk, and Emerging Therapies.Molecular neurobiology · 2026Review
- Astrocytic connexin 43 hemichannel dysregulation drives prefrontal circuit dysfunction and schizophrenia-like behaviors.Molecular psychiatry · 2026Article
- Connexin 50 mediates disease-relevant alpha-synuclein oligomer propagation and neuroinflammation in neurodegenerative disease.iScience · 2026Article
- Signaling cascades shape functional subpopulations of cortical astrocytes in male wild-type mice and APP/PS1dE9 Alzheimer's disease model.Nature communications · 2026Article
- Curing the brain: in search for new astrocyte-specific therapies.Experimental & molecular medicine · 2026Review
- Inhibition of connexin hemichannels protects retinal ganglion cells against ocular nerve injury.Cellular and molecular life sciences : CMLS · 2026Article
- Astrocytic KFrontiers in aging neuroscience · 2026Review
- Are Insulin and Metformin Really Protective on Amyotrophic Lateral Sclerosis by Blocking the Astrocytic Cx43 Channel?Chronic diseases and translational medicine · 2025Article
- Facilitated α-synuclein oligomer sharing among glial cells by a centrally acting connexin inhibitor attenuates a rapidly progressive multiple system atrophy-cerebellar type model by reducing the neuronal α-synuclein burden.Acta neuropathologica communications · 2025Article
- Activity and Heterogeneity of Astrocytes in Neurological Diseases: Molecular Mechanisms and Therapeutic Targets.MedComm · 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
- Inorganic Polyphosphate: An Emerging Regulator of Neuronal Bioenergetics and Its Implications in Neuroprotection.Biomolecules · 2025Review
- Insulin and Metformin are Associated With Reduced Risk of Amyotrophic Lateral Sclerosis.Chronic diseases and translational medicine · 2025Article
- Acupuncture regulates astrocyte neurotoxic polarization to protect blood-brain barrier integrity in delayed thrombolysis through mediating ERK1/2/Cx43 axis.IBRO neuroscience reports · 2025Article
- Review
- Astrocytes Lingering at a Crossroads: Neuroprotection and Neurodegeneration in Neurocognitive Dysfunction.International journal of biological sciences · 2025Review
- Boldine as a neuroprotective agent against motor neuron degeneration in models of amyotrophic lateral sclerosis.Frontiers in cellular neuroscience · 2025Article
- Hydrogen Sulfide Modulates Astrocytic Toxicity in Mouse Spinal Cord Cultures: Implications for Amyotrophic Lateral Sclerosis.Antioxidants (Basel, Switzerland) · 2024Article
Corrections and comments
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Authors and funding
16 authors at 3 institutions in 1 country.
Funding
Abstract
Connexin 43 (Cx43) gap junctions and hemichannels mediate astrocyte intercellular communication in the central nervous system under normal conditions and contribute to astrocyte-mediated neurotoxicity in amyotrophic lateral sclerosis (ALS). Here, we show that astrocyte-specific knockout of Cx43 in a mouse model of ALS slows disease progression both spatially and temporally, provides motor neuron (MN) protection, and improves survival. In addition, Cx43 expression is up-regulated in human postmortem tissue and cerebrospinal fluid from ALS patients. Using human induced pluripotent stem cell–derived astrocytes (hiPSC-A) from both familial and sporadic ALS, we establish that Cx43 is up-regulated and that Cx43-hemichannels are enriched at the astrocyte membrane. We also demonstrate that the pharmacological blockade of Cx43-hemichannels in ALS astrocytes using GAP 19, a mimetic peptide blocker, and tonabersat, a clinically tested small molecule, provides neuroprotection of hiPSC-MN and reduces ALS astrocyte-mediated neuronal hyperexcitability. Extending the in vitro application of tonabersat with chronic administration to SOD1G93A mice results in MN protection with a reduction in reactive astrocytosis and microgliosis. Taking these data together, our studies identify Cx43 hemichannels as conduits of astrocyte-mediated disease progression and a pharmacological target for disease-modifying ALS therapies.
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Registered trials
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