Wildtype motoneurons, ALS‐Linked SOD1 mutation and glutamate profoundly modify astrocyte metabolism and lactate shuttling

Hounoum, Blandine Madji; Mavel, Sylvie; Coque, Emmanuelle; Patin, Franck; Vourc’h, Patrick; Marouillat, Sylviane; Nadal-Desbarats, Lydie; Emond, Patrick; Corcia, Philippe; Andres, Christian R.; Raoul, Cédric; Blasco, Hélène

doi:10.1002/glia.23114

Cited by 59 publications

(46 citation statements)

References 63 publications

(88 reference statements)

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“…Increased lactate production upon NA stimulation in astrocytes with TDP-43 inclusions may lead to a better metabolic support of neurons with lactate due to lactate flux generated between astrocytes and neurons 77 . This www.nature.com/scientificreports www.nature.com/scientificreports/ is, however, contradictory to the CNS hypometabolism observed in patients with neurodegenerative diseases, including ALS 43,45 . Recently, decreased expression of lactate MCT1 and MCT4 transporters has been reported post mortem in the motor cortex of ALS patients compared to non-ALS patients 78 .…”

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confidence: 70%

“…Thus, despite facilitated NA-mediated aerobic glycolysis in astrocytes with TDP-43 inclusions, lactate may accumulate inside cells, and the metabolic support of neurons in patients may be decreased significantly contributing to neuron degeneration in ALS and FTD-U. Consistent with this hypothesis, cAMP signaling and lactate homeostasis in the brain were noted to be reduced in patients with some forms of ALS 43,45 .…”

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confidence: 75%

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Astrocytes with TDP-43 inclusions exhibit reduced noradrenergic cAMP and Ca2+ signaling and dysregulated cell metabolism

Velebit

Horvat

Smolič

et al. 2020

Sci Rep

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Most cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) have cytoplasmic inclusions of TAR DNA-binding protein 43 (TDP-43) in neurons and non-neuronal cells, including astrocytes, which metabolically support neurons with nutrients. Neuronal metabolism largely depends on the activation of the noradrenergic system releasing noradrenaline. Activation of astroglial adrenergic receptors with noradrenaline triggers cAMP and Ca 2+ signaling and augments aerobic glycolysis with production of lactate, an important neuronal energy fuel. Astrocytes with cytoplasmic TDP-43 inclusions can cause motor neuron death, however, whether astroglial metabolism and metabolic support of neurons is altered in astrocytes with TDP-43 inclusions, is unclear. We measured lipid droplet and glucose metabolisms in astrocytes expressing the inclusion-forming C-terminal fragment of TDP-43 or the wild-type TDP-43 using fluorescent dyes or genetically encoded nanosensors. Astrocytes with TDP-43 inclusions exhibited a 3-fold increase in the accumulation of lipid droplets versus astrocytes expressing wild-type TDP-43, indicating altered lipid droplet metabolism. In these cells the noradrenaline-triggered increases in intracellular cAMP and Ca 2+ levels were reduced by 35% and 31%, respectively, likely due to the downregulation of β 2-adrenergic receptors. Although noradrenaline triggered a similar increase in intracellular lactate levels in astrocytes with and without TDP-43 inclusions, the probability of activating aerobic glycolysis was facilitated by 1.6-fold in astrocytes with TDP-43 inclusions and lactate MCT1 transporters were downregulated. Thus, while in astrocytes with TDP-43 inclusions noradrenergic signaling is reduced, aerobic glycolysis and lipid droplet accumulation are facilitated, suggesting dysregulated astroglial metabolism and metabolic support of neurons in TDP-43-associated ALS and FTD. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the loss of both upper and lower motor neurons in the brain and spinal cord, and by the progressive paralysis of voluntary muscles and death 1,2. The pathologic hallmark of ALS are cytoplasmic inclusions in motor neurons. In most cases (~95%) of sporadic and familial ALS, TAR DNA-binding protein 43 (TDP-43), encoded by the TARDBP gene, has been identified as the key component of these inclusions 1-9. Moreover, TDP-43 has also been identified as the major protein in inclusions in frontotemporal dementia with ubiquitin-positive inclusions (FTD-U) 2,6. TDP-43 is a highly conserved protein (414 amino acids), ubiquitously expressed in all tissues and under physiological conditions, primarily localized to the nucleus; however, low levels are also present in the cytoplasm 2,3,8,10-13. TDP-43, an RNA-binding protein, is implicated in multiple aspects of RNA processing, including regulation of transcription, splicing, transport, and stabilization of mRNAs. It also regulates microRNA biogenesis and interacts with DNA. Therefore, its perturbance ...

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confidence: 70%

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confidence: 75%

Astrocytes with TDP-43 inclusions exhibit reduced noradrenergic cAMP and Ca2+ signaling and dysregulated cell metabolism

Velebit

Horvat

Smolič

et al. 2020

Sci Rep

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“…Reduced number of astrocytic glutamate transporters resulted in dysfunctional glutamate cycling, leading to hyperexcitability of the motor neurons and subsequent death (Do-Ha et al, 2018). Aberrant calcium signaling and loss of lactate shuttling between the neurons and reactive astrocytes also propagate the disease severity (Madji Hounoum et al, 2017). In addition, increased transforming growth factor-β1 (TGF-β1) released by the neurotoxic astrocytes also compromised the neuroprotective role of microglia and infiltrating immune cells (Endo et al, 2015).…”

Section: Neurodegenerative Diseasementioning

confidence: 99%

Metabolic Regulation of Glial Phenotypes: Implications in Neuron–Glia Interactions and Neurological Disorders

Afridi

Kim

Rahman

et al. 2020

Front. Cell. Neurosci.

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Glial cells are multifunctional, non-neuronal components of the central nervous system with diverse phenotypes that have gained much attention for their close involvement in neuroinflammation and neurodegenerative diseases. Glial phenotypes are primarily characterized by their structural and functional changes in response to various stimuli, which can be either neuroprotective or neurotoxic. The reliance of neurons on glial cells is essential to fulfill the energy demands of the brain for its proper functioning. Moreover, the glial cells perform distinct functions to regulate their own metabolic activities, as well as work in close conjunction with neurons through various secreted signaling or guidance molecules, thereby constituting a complex network of neuron-glial interactions in health and disease. The emerging evidence suggests that, in disease conditions, the metabolic alterations in the glial cells can induce structural and functional changes together with neuronal dysfunction indicating the importance of neuron-glia interactions in the pathophysiology of neurological disorders. This review covers the recent developments that implicate the regulation of glial phenotypic changes and its consequences on neuron-glia interactions in neurological disorders. Finally, we discuss the possibilities and challenges of targeting glial metabolism as a strategy to treat neurological disorders.

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“…Decreased expression of the astrocytic lactate transporter (monocarboxylate transporter 4, MCT4/Slc16a4) and decreased lactate spinal cord levels have been described in hSOD1 G93A mice [74]. Mutant hSOD1-expressing astrocytes display significant alterations of their metabolic fingerprint and altered cellular lactate shuttling function when in co-culture with motor neurons [103, 104]. Accordingly, lactate supplementation rescues motor neurons in co-culture with hSOD1 G93A astrocytes [74].…”

Section: Pathways Involved In Astrocyte-mediated Motor Neuron Toximentioning

confidence: 99%

Role and Therapeutic Potential of Astrocytes in Amyotrophic Lateral Sclerosis

Pehar

Harlan

Killoy

et al. 2018

CPD

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Amyotrophic lateral sclerosis (ALS) is characterized by the progressive degeneration of motor neurons in the spinal cord, brain stem, and motor cortex. The molecular mechanism underlying the progressive degeneration of motor neuron remains uncertain but involves a non-cell autonomous process. In acute injury or degenerative diseases astrocytes adopt a reactive phenotype known as astrogliosis. Astrogliosis is a complex remodeling of astrocyte biology and most likely represents a continuum of potential phenotypes that affect neuronal function and survival in an injury-specific manner. In ALS patients, reactive astrocytes surround both upper and lower degenerating motor neurons and play a key role in the pathology. It has become clear that astrocytes play a major role in ALS pathology. Through loss of normal function or acquired new characteristics, astrocytes are able to influence motor neuron fate and the progression of the disease. The use of different cell culture models indicates that ALS-astrocytes are able to induce motor neuron death by secreting a soluble factor(s). Here, we discuss several pathogenic mechanisms that have been proposed to explain astrocyte-mediated motor neuron death in ALS. In addition, examples of strategies that revert astrocyte-mediated motor neuron toxicity are reviewed to illustrate the therapeutic potential of astrocytes in ALS. Due to the central role played by astrocytes in ALS pathology, therapies aimed at modulating astrocyte biology may contribute to the development of integral therapeutic approaches to halt ALS progression.

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Wildtype motoneurons, ALS‐Linked SOD1 mutation and glutamate profoundly modify astrocyte metabolism and lactate shuttling

Cited by 59 publications

References 63 publications

Astrocytes with TDP-43 inclusions exhibit reduced noradrenergic cAMP and Ca2+ signaling and dysregulated cell metabolism

Astrocytes with TDP-43 inclusions exhibit reduced noradrenergic cAMP and Ca2+ signaling and dysregulated cell metabolism

Metabolic Regulation of Glial Phenotypes: Implications in Neuron–Glia Interactions and Neurological Disorders

Role and Therapeutic Potential of Astrocytes in Amyotrophic Lateral Sclerosis

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