ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2015
Dysregulation of glutamine transporter SNAT1 in Rett syndrome microglia: a mechanism for mitochondrial dysfunction and neurotoxicity.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 63 papers.
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Who cites it
63 citing papers in PubMed, 88 citations in OpenAlex.
- Flipping the Switch: MeCP2-Mediated Lactylation Rewires Microglial Metabolism and Inflammation via the HK2/mTOR Axis in Poststroke Neuroinflammation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
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- Comparative Analysis of Hypothalamic Responses to Stress and Glutamine Supplementation in Diet-Induced Obese Mice: A Study of Sex Differences.Inflammation · 2026Article
- Toward an NGF-based therapy for Rett syndrome.Frontiers in neuroscience · 2026Review
- Metabolic Flexibility of Microglia: Energy Substrate Utilization and Impact on Neuronal Metabolism.Journal of neurochemistry · 2025Article
- The Role of GABA Pathway Components in Pathogenesis of Neurodevelopmental Disorders.International journal of molecular sciences · 2025Review
- MECP2 Dysfunction in Rett Syndrome: Molecular Mechanisms, Multisystem Pathology, and Emerging Therapeutic Strategies.International journal of molecular sciences · 2025Review
- CNS resident macrophages exhibit region-specific states and immunogenic responses during Rbpj-deficient brain arteriovenous malformation.Scientific reports · 2025Article
- Fundamental Neurochemistry Review: Lipids across microglial states.Journal of neurochemistry · 2025Review
- Review
- The impact of mild episodic ketosis on microglia and hippocampal long-term depression in 5xFAD mice.FASEB bioAdvances · 2024Article
- Human microglial cells as a therapeutic target in a neurodevelopmental disease model.Stem cell reports · 2024Article
- Dendrimer nanotherapy targeting of glial dysfunction improves inflammation and neurobehavioral phenotype in adult female Mecp2-heterozygous mouse model of Rett syndrome.Journal of neurochemistry · 2024Article
- RIPK1 activation in Mecp2-deficient microglia promotes inflammation and glutamate release in RTT.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- The ketone body β-hydroxybutyrate shifts microglial metabolism and suppresses amyloid-β oligomer-induced inflammation in human microglia.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2023Article
- Metabolic regulation of microglial phagocytosis: Implications for Alzheimer's disease therapeutics.Translational neurodegeneration · 2023Review
- Mitochondrial modulation with leriglitazone as a potential treatment for Rett syndrome.Journal of translational medicine · 2023Article
- Microglial Metabolic Reprogramming: Emerging Insights and Therapeutic Strategies in Neurodegenerative Diseases.Cellular and molecular neurobiology · 2023Review
- Blood-Brain Barrier Integrity Is Perturbed in aBiomolecules · 2023Article
- Neuron-specific transcriptomic signatures indicate neuroinflammation and altered neuronal activity in ASD temporal cortex.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
3 more citing papers are in PubMed but not listed here.
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Authors and funding
7 authors at 5 institutions in 2 countries.
Funding
Abstract
Rett syndrome (RTT) is an autism spectrum disorder caused by loss-of-function mutations in the gene encoding MeCP2, an epigenetic modulator that binds the methyl CpG dinucleotide in target genes to regulate transcription. Previously, we and others reported a role of microglia in the pathophysiology of RTT. To understand the mechanism of microglia dysfunction in RTT, we identified a MeCP2 target gene, SLC38A1, which encodes a major glutamine transporter (SNAT1), and characterized its role in microglia. We found that MeCP2 acts as a microglia-specific transcriptional repressor of SNAT1. Because glutamine is mainly metabolized in the mitochondria, where it is used as an energy substrate and a precursor for glutamate production, we hypothesize that SNAT1 overexpression in MeCP2-deficient microglia would impair the glutamine homeostasis, resulting in mitochondrial dysfunction as well as microglial neurotoxicity because of glutamate overproduction. Supporting this hypothesis, we found that MeCP2 downregulation or SNAT1 overexpression in microglia resulted in (1) glutamine-dependent decrease in microglial viability, which was corroborated by reduced microglia counts in the brains of MECP2 knock-out mice; (2) proliferation of mitochondria and enhanced mitochondrial production of reactive oxygen species; (3) increased oxygen consumption but decreased ATP production (an energy-wasting state); and (4) overproduction of glutamate that caused NMDA receptor-dependent neurotoxicity. The abnormalities could be rectified by mitochondria-targeted expression of catalase and a mitochondria-targeted peptide antioxidant, Szeto-Schiller 31. Our results reveal a novel mechanism via which MeCP2 regulates bioenergetic pathways in microglia and suggest a therapeutic potential of mitochondria-targeted antioxidants for RTT.
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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.