ArticleThe Journal of clinical investigation2019
Membralin deficiency dysregulates astrocytic glutamate homeostasis leading to ALS-like impairment.
Article in The Journal of clinical investigation, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers, 2 of them syntheses that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
32 citing papers in PubMed, 2 syntheses or guidelines pooled it, 43 citations in OpenAlex.
- The Current Potential Pathogenesis of Amyotrophic Lateral Sclerosis.Molecular neurobiology · 2025Pooled it
- Meta-analysis of human and mouse ALS astrocytes reveals multi-omic signatures of inflammatory reactive states.Genome research · 2022Pooled it
- JP1 peptide modulates oxidative stress and autophagy via Keap1-Nrf2-ARE in ALS model mice.BMC medicine · 2026Article
- Altered astrocyte-neuron crosstalk in progressive supranuclear palsy: integrated evidence from proteomics and magnetic resonance spectroscopy.Acta neuropathologica · 2026Article
- Therapeutic potential ofMicrobiome research reports · 2026Article
- Molecular mechanisms of excitotoxicity and their relevance to the pathogenesis of neurodegenerative diseases-an update.Acta pharmacologica Sinica · 2025Review
- Activity and Heterogeneity of Astrocytes in Neurological Diseases: Molecular Mechanisms and Therapeutic Targets.MedComm · 2025Review
- Review
- Glutamate, a Key for Astrocytes to Participate in Brain Function and Diseases.Neurochemical research · 2025Review
- Ectopic expression of Slc1a2 in the prefrontal cortex of sleep-deprived male mice counteracts the glutamate/GABA-glutamine dysfunction.BMC biology · 2025Article
- Review
- Tapasin assembly surveillance by the RNF185/Membralin ubiquitin ligase complex regulates MHC-I surface expression.Nature communications · 2024Article
- Membralin is required for maize development and defines a branch of the endoplasmic reticulum-associated degradation pathway in plants.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- TNF-α/TNFR1 activated astrocytes exacerbate depression-like behavior in CUMS mice.Cell death discovery · 2024Article
- The Diverse Roles of Reactive Astrocytes in the Pathogenesis of Amyotrophic Lateral Sclerosis.Brain sciences · 2024Review
- Pathomechanistic Networks of Motor System Injury in Amyotrophic Lateral Sclerosis.Current neuropharmacology · 2024Review
- Review
- Functional roles of reactive astrocytes in neuroinflammation and neurodegeneration.Nature reviews. Neurology · 2023Review
- A Medicinal Chemistry Perspective on Excitatory Amino Acid Transporter 2 Dysfunction in Neurodegenerative Diseases.Journal of medicinal chemistry · 2023Review
- Microglial crosstalk with astrocytes and immune cells in amyotrophic lateral sclerosis.Frontiers in immunology · 2023Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
17 authors at 3 institutions in 2 countries.
Funding
Abstract
Mechanisms underlying motor neuron degeneration in amyotrophic lateral sclerosis (ALS) are yet unclear. Specific deletion of the ER-component membralin in astrocytes manifested postnatal motor defects and lethality in mice, causing the accumulation of extracellular glutamate through reducing the glutamate transporter EAAT2. Restoring EAAT2 levels in membralin KO astrocytes limited astrocyte-dependent excitotoxicity in motor neurons. Transcriptomic profiles from mouse astrocytic membralin KO motor cortex indicated significant perturbation in KEGG pathway components related to ALS, including downregulation of Eaat2 and upregulation of Tnfrsf1a. Changes in gene expression with membralin deletion also overlapped with mouse ALS models and reactive astrocytes. Our results shown that activation of TNF receptor (TNFR1)-NFκB pathway known to suppress Eaat2 transcription was upregulated with membralin deletion. Further, reduced membralin and EAAT2 levels correlated with disease progression in spinal cord from SOD1-mutant mouse models, and reductions in membralin/EAAT2 were observed in human ALS spinal cord. Importantly, overexpression of membralin in SOD1G93A astrocytes decreased TNFR1 levels and increased EAAT2 expression, and improved motor neuron survival. Importantly, upregulation of membralin in SOD1G93A mice significantly prolonged mouse survival. Together, our study provided a mechanism for ALS pathogenesis where membralin limited glutamatergic neurotoxicity, suggesting that modulating membralin had potentials in ALS therapy.
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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.