ArticleGlia2011
Motor neuron impairment mediated by a sumoylated fragment of the glial glutamate transporter EAAT2.
Article in Glia, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 64 citations in OpenAlex.
- Bridging the gap: neuroinflammation and the dawn of precision medicine in amyotrophic lateral sclerosis.Translational neurodegeneration · 2026Review
- Glial Cells as Key Mediators in the Pathophysiology of Neurodegenerative Diseases.International journal of molecular sciences · 2026Review
- In Vitro Models of Amyotrophic Lateral Sclerosis.Cellular and molecular neurobiology · 2023Review
- Impact of Plant-Derived Compounds on Amyotrophic Lateral Sclerosis.Neurotoxicity research · 2023Review
- Uncoupling the Excitatory Amino Acid Transporter 2 From Its C-Terminal Interactome Restores Synaptic Glutamate Clearance at Corticostriatal Synapses and Alleviates Mutant Huntingtin-Induced Hypokinesia.Frontiers in cellular neuroscience · 2021Article
- The impact of proteostasis dysfunction secondary to environmental and genetic causes on neurodegenerative diseases progression and potential therapeutic intervention.Environmental science and pollution research international · 2020Review
- Glial Cells-The Strategic Targets in Amyotrophic Lateral Sclerosis Treatment.Journal of clinical medicine · 2020Review
- Mitochondrial Dysfunction, Neurogenesis, and Epigenetics: Putative Implications for Amyotrophic Lateral Sclerosis Neurodegeneration and Treatment.Frontiers in neuroscience · 2020Review
- Transcriptomics and Metabolomics in Amyotrophic Lateral Sclerosis.Advances in experimental medicine and biology · 2020Review
- The role of astrocytic glutamate transporters GLT-1 and GLAST in neurological disorders: Potential targets for neurotherapeutics.Neuropharmacology · 2019Review
- Enhanced Function and Overexpression of Metabotropic Glutamate Receptors 1 and 5 in the Spinal Cord of the SOD1International journal of molecular sciences · 2019Article
- Post-translational Regulation of GLT-1 in Neurological Diseases and Its Potential as an Effective Therapeutic Target.Frontiers in molecular neuroscience · 2019Review
- Post-translational modifications of transporters.Pharmacology & therapeutics · 2018Review
- HSPB1 mutations causing hereditary neuropathy in humans disrupt non-cell autonomous protection of motor neurons.Experimental neurology · 2017Article
- Mutation of the caspase-3 cleavage site in the astroglial glutamate transporter EAAT2 delays disease progression and extends lifespan in the SOD1-G93A mouse model of ALS.Experimental neurology · 2017Article
- Oxidative Stress in Neurodegenerative Diseases: From Molecular Mechanisms to Clinical Applications.Oxidative medicine and cellular longevity · 2017Review
- EAAT2 and the Molecular Signature of Amyotrophic Lateral Sclerosis.Advances in neurobiology · 2017Review
- Astrocytes and Microglia as Non-cell Autonomous Players in the Pathogenesis of ALS.Experimental neurobiology · 2016Review
- Article
- Battling Alzheimer's Disease: Targeting SUMOylation-Mediated Pathways.Neurochemical research · 2016Review
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
Abstract
Dysregulation of glutamate handling ensuing downregulation of expression and activity levels of the astroglial glutamate transporter EAAT2 is implicated in excitotoxic degeneration of motor neurons in amyotrophic lateral sclerosis (ALS). We previously reported that EAAT2 (a.k.a. GLT-1) is cleaved by caspase-3 at its cytosolic carboxy-terminus domain. This cleavage results in impaired glutamate transport activity and generates a proteolytic fragment (CTE) that we found to be post-translationally conjugated by SUMO1. We show here that this sumoylated CTE fragment accumulates in the nucleus of spinal cord astrocytes of the SOD1-G93A mouse model of ALS at symptomatic stages of disease. Astrocytic expression of CTE, artificially tagged with SUMO1 (CTE-SUMO1) to mimic the native sumoylated fragment, recapitulates the nuclear accumulation pattern of the endogenous EAAT2-derived proteolytic fragment. Moreover, in a co-culture binary system, expression of CTE-SUMO1 in spinal cord astrocytes initiates extrinsic toxicity by inducing caspase-3 activation in motor neuron-derived NSC-34 cells or axonal growth impairment in primary motor neurons. Interestingly, prolonged nuclear accumulation of CTE-SUMO1 is intrinsically toxic to spinal cord astrocytes, although this gliotoxic effect of CTE-SUMO1 occurs later than the indirect, noncell autonomous toxic effect on motor neurons. As more evidence on the implication of SUMO substrates in neurodegenerative diseases emerges, our observations strongly suggest that the nuclear accumulation in spinal cord astrocytes of a sumoylated proteolytic fragment of the astroglial glutamate transporter EAAT2 could participate to the pathogenesis of ALS and suggest a novel, unconventional role for EAAT2 in motor neuron degeneration.
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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.