ArticleExperimental neurology2017
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.
Article in Experimental neurology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 38 citations in OpenAlex.
- Neutralization of pathogenic PC-OxPL by AAV-delivered scFv as a therapeutic strategy for amyotrophic lateral sclerosis.Molecular therapy. Advances · 2026Article
- 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
- Excitatory Amino Acid Transporters as Therapeutic Targets in the Treatment of Neurological Disorders: Their Roles and Therapeutic Prospects.Neurochemical research · 2025Review
- Glutamate uptake is transiently compromised in the perilesional cortex following controlled cortical impact.Cerebral cortex (New York, N.Y. : 1991) · 2025Article
- HDAC7 knockout mitigates astrocyte reactivity and neuroinflammation via the IRF3/cGAS/STING signaling pathway.Frontiers in cellular neuroscience · 2025Article
- Pathomechanistic Networks of Motor System Injury in Amyotrophic Lateral Sclerosis.Current neuropharmacology · 2024Review
- Astrocyte-Neuron Interactions Contributing to Amyotrophic Lateral Sclerosis Progression.Advances in neurobiology · 2024Review
- The Key Role of Astrocytes in Amyotrophic Lateral Sclerosis and Their Commitment to Glutamate Excitotoxicity.International journal of molecular sciences · 2023Review
- A Medicinal Chemistry Perspective on Excitatory Amino Acid Transporter 2 Dysfunction in Neurodegenerative Diseases.Journal of medicinal chemistry · 2023Review
- Current insights in the molecular genetic pathogenesis of amyotrophic lateral sclerosis.Frontiers in neuroscience · 2023Review
- Patching Up the Permeability: The Role of Stem Cells in Lessening Neurovascular Damage in Amyotrophic Lateral Sclerosis.Stem cells translational medicine · 2022Review
- Immune-microbiome interplay and its implications in neurodegenerative disorders.Metabolic brain disease · 2022Review
- 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
- Microbial Infections Are a Risk Factor for Neurodegenerative Diseases.Frontiers in cellular neuroscience · 2021Review
- The role of astrocytes in oxidative stress of central nervous system: A mixed blessing.Cell proliferation · 2020Review
- Glial Cells-The Strategic Targets in Amyotrophic Lateral Sclerosis Treatment.Journal of clinical medicine · 2020Review
- The role of astrocytic glutamate transporters GLT-1 and GLAST in neurological disorders: Potential targets for neurotherapeutics.Neuropharmacology · 2019Review
- Post-translational Regulation of GLT-1 in Neurological Diseases and Its Potential as an Effective Therapeutic Target.Frontiers in molecular neuroscience · 2019Review
- Glutamate Excitotoxicity Linked to Spermine Oxidase Overexpression.Molecular neurobiology · 2018Article
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
Downregulation in the astroglial glutamate transporter EAAT2 in amyotrophic lateral sclerosis (ALS) patients and mutant SOD1 mouse models of ALS is believed to contribute to the death of motor neurons by excitotoxicity. We previously reported that caspase-3 cleaves EAAT2 at a unique cleavage consensus site located in its c-terminus domain, a proteolytic cleavage that also occurs in vivo in the mutant SOD1 mouse model of ALS and leads to accumulation of a sumoylated EAAT2 C-terminus fragment (CTE-SUMO1) beginning around onset of disease. CTE-SUMO1 accumulates in PML nuclear bodies of astrocytes and causes them to alter their mature phenotypes and secrete factors toxic to motor neurons. Here, we report that mutating the caspase-3 consensus site in the EAAT2 sequence with an aspartate to asparagine mutation (D504N), thereby inhibiting caspase-3 cleavage of EAAT2, confers protection to the SOD1-G93A mouse. EAAT2-D504N knock-in mutant mice were generated and crossed with SOD1-G93A mice to assess the in vivo pathogenic relevance for ALS symptoms of EAAT2 cleavage. The mutation did not affect normal EAAT2 function nor non-ALS mice. In agreement with the timing of CTE-SUMO1 accumulation, while onset of disease was not affected, the mutation caused an extension in progression time, a delay in the development of hindlimb and forelimb muscle weakness, and a significant increase in the lifespan of SOD1-G93A mice.
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