Glial Glutamine Homeostasis in Health and Disease

Andersen, Jens V.; Schousboe, Arne

doi:10.1007/s11064-022-03771-1

Cited by 31 publications

(22 citation statements)

References 421 publications

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“…The neuroprotective effect of Nrf2 overexpression might not require Nrf2 delivery to neurons [ 132 ], and in such cases, the promotion of Nrf2 expression in astrocytes could be a worthwhile approach for protecting neurons [ 153 ]. This point of elucidation is fundamental considering the established role of astrocytes in the diseased brain, including HD [ 154 ]. Among the substances reported, only the TP derivative CDDO-MA was tested in cells, rat 3-NP HD models, and in the transgenic animal model of HD (N171-82Q mice) ( Figure 3 ).…”

Section: Nrf2 Activators To Treat Hd: Outlooksmentioning

confidence: 99%

Nrf2 Pathway in Huntington’s Disease (HD): What Is Its Role?

Tucci

Lattanzi

Severini

et al. 2022

IJMS

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Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease that occurs worldwide. Despite some progress in understanding the onset of HD, drugs that block or delay symptoms are still not available. In recent years, many treatments have been proposed; among them, nuclear transcriptional factor-2 (Nrf2) enhancer compounds have been proposed as potential therapeutic agents to treat HD. Nrf2 triggers an endogenous antioxidant pathway activated in different neurodegenerative disorders. Probably, the stimulation of Nrf2 during either the early phase or before HD symptoms’ onset, could slow or prevent striatum degeneration. In this review, we present the scientific literature supporting the role of Nrf2 in HD and the potential prophylactic and therapeutic role of this compound.

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Section: Nrf2 Activators To Treat Hd: Outlooksmentioning

confidence: 99%

Nrf2 Pathway in Huntington’s Disease (HD): What Is Its Role?

Tucci

Lattanzi

Severini

et al. 2022

IJMS

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“…Nevertheless, free amino acids are present in the milieu of early developing embryos (Van Winkle., 2021) and human cord blood at term contains glutamate, with levels increased in the presence of fetal distress (Perez-Mato et al, 2016). In the central nervous system, astrocytes synthesize and release glutamine that is taken up by neurons to generate glutamate to be used in neurotransmission (Anderson and Schousboe, 2022). Whether a similar glutamate-producing mechanism operates in the kidney is not known.…”

Section: Discussionmentioning

confidence: 99%

Human pluripotent stem cell-derived kidney organoids reveal tubular epithelial pathobiology of heterozygousHNF1B-associated dysplastic kidney malformations

Bantounas

Rooney

Lopes

et al. 2023

Preprint

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Hepatocyte nuclear factor 1B (HNF1B) encodes a transcription factor expressed in developing human kidney epithelia. Heterozygous HNF1B mutations are the commonest monogenic cause of dysplastic kidney malformations (DKMs). To understand their pathobiology, we generated heterozygous HNF1B mutant kidney organoids from CRISPR-Cas9 gene-edited human ESCs and iPSCs reprogrammed from a family with HNF1B-asscociated DKMs. Mutant organoids contained enlarged malformed tubules and displayed deregulated cell turnover. Numerous genes implicated in Mendelian kidney tubulopathies were downregulated, and mutant tubules resisted the cAMP-mediated dilatation seen in controls. Bioinformatic analyses indicated abnormal WNT, calcium, and glutamatergic pathways, the latter hitherto unstudied in developing kidneys. Glutamate ionotropic receptor kainate type subunit 3 was upregulated in mutant organoids and was detected in their tubules and in fetal human DKM dysplastic epithelia. These results reveal morphological, molecular, and physiological roles for HNF1B in human kidney tubule morphogenesis and functional differentiation. They additionally suggest druggable targets to ameliorate disease.

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“…In contrast, no viable model of GAT3 deletion has yet been reported (MouseGenomeInformatics, 2005; Zhou & Danbolt, 2013), which may suggest that astrocyte GAT3 function is indispensable. Note that, not only transporters of glutamate and GABA but also of glutamine are essential to sustain neurotransmitter recycling between neurons and astrocytes (Figure 2) (Andersen & Schousboe, 2023; Leke & Schousboe, 2016).…”

Section: Cellular Transport Of Glutamate and Gabamentioning

confidence: 99%

“…Although the expression and activity of PAG are higher in neurons than in astrocytes (Hogstad et al, 1988; Laake et al, 1999), active astrocyte glutamine metabolism has been functionally demonstrated (Huang & Hertz, 1995; McKenna, Tildon, et al, 1996; Sonnewald, Westergaard, et al, 1996). Astrocyte PAG expression was recently confirmed in a subset of astrocytes in vivo (Cardona et al, 2015), which may provide these cells with a metabolic flexibility, but the exact physiological functions remain unclear (Andersen & Schousboe, 2023).…”

Section: Metabolism Of Glutamate and Gabamentioning

confidence: 99%

“…To account for the loss of neuronal glutamate and GABA, caused by astrocyte uptake and cellular metabolism, astrocytes provide neurons with glutamine. Glutamine is a highly abundant cerebral amino acid and astrocyte glutamine support is imperative for brain function (Albrecht et al, 2007; Andersen & Schousboe, 2023). Cerebral glutamine synthesis and metabolism are catalyzed by the essential enzymes glutamine synthetase (GS) and phosphate‐activated glutaminase (PAG), respectively (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

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Milestone Review: Metabolic dynamics of glutamate and GABA mediated neurotransmission — The essential roles of astrocytes

Andersen

Schousboe

2023

Journal of Neurochemistry

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Since it was first generally accepted that the two amino acids glutamate and GABA act as principal neurotransmitters, several landmark discoveries relating to this function have been uncovered. Synaptic homeostasis of these two transmitters involves several cell types working in close collaboration and is facilitated by specialized cellular processes. Notably, glutamate and GABA are extensively recycled between neurons and astrocytes in a process known as the glutamate/GABA-glutamine cycle, which is essential to maintain synaptic transmission. The glutamate/GABAglutamine cycle is intimately coupled to cellular energy metabolism and relies on the metabolic function of both neurons and astrocytes. Importantly, astrocytes display unique metabolic features allowing extensive metabolite release, hereby providing metabolic support for neurons. Furthermore, astrocytes undergo complex metabolic adaptations in response to injury and pathology, which may greatly affect the glutamate/GABA-glutamine cycle and synaptic transmission during disease. In this Milestone Review we outline major discoveries in relation to synaptic balancing of glutamate and GABA signaling, including cellular uptake, metabolism, and recycling.We provide a special focus on how astrocyte function and metabolism contribute to sustain neuronal transmission through metabolite transfer. Recent advances on cellular glutamate and GABA homeostasis are reviewed in the context of brain pathology, including glutamate toxicity and neurodegeneration. Finally, we consider how pathological astrocyte metabolism may serve as a potential target of metabolic intervention. Integrating the multitude of fine-tuned cellular processes supporting neurotransmitter recycling, will aid the next generation of major discoveries on brain glutamate and GABA homeostasis.

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Glial Glutamine Homeostasis in Health and Disease

Cited by 31 publications

References 421 publications

Nrf2 Pathway in Huntington’s Disease (HD): What Is Its Role?

Nrf2 Pathway in Huntington’s Disease (HD): What Is Its Role?

Human pluripotent stem cell-derived kidney organoids reveal tubular epithelial pathobiology of heterozygousHNF1B-associated dysplastic kidney malformations

Milestone Review: Metabolic dynamics of glutamate and GABA mediated neurotransmission — The essential roles of astrocytes

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