IFNγ triggers a LIGHT-dependent selective death of motoneurons contributing to the non-cell-autonomous effects of mutant SOD1

Aebischer, Julianne; Cassina, Patricia; Otsmane, Belkacem; Moumen, Anice; Seilhean, Danielle; Meininger, Vincent; Barbeito, Luis; Pettmann, Brigitte; Raoul, Cédric

doi:10.1038/cdd.2010.143

Cited by 71 publications

(106 citation statements)

References 49 publications

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“…The death outcome of the somatic LIGHT signal is consistent with the increased levels of LIGHT in the spinal cord associated with motoneuron degeneration in ALS [5,6]. To confirm that upregulation of LIGHT in the spinal cord is associated with motoneuron death, we conducted a sciatic nerve axotomy that led to motoneuron death along with an upregulation of IFN-c ( Supplementary Fig S3A-D).…”

Section: Regional Activation Of Light-dependent Signaling Triggers Opmentioning

confidence: 53%

“…Motoneurons were isolated from embryonic day (E) 12.5 mice of indicated genotype as previously described [5]. Microfluidic devices were prepared as described in [10].…”

Section: Methodsmentioning

confidence: 99%

“…When added to the culture medium for 24 or 48 h, agonistic anti-LT-bR antibodies [5] increased both axon outgrowth and number of branch points as efficiently as sLIGHT (Fig 1J, K and Supplementary Fig S1G, H). However, the blockade of LIGHT-HVEM interaction by antagonistic anti-HVEM antibodies [8] did not affect motoneuron axons (Fig 1J, K and Supplementary Fig S1G, H).…”

Section: Light Promotes Axon Outgrowth and Branching In Motoneuronsmentioning

confidence: 97%

“…As previously demonstrated, activation of LT-bR by recombinant soluble LIGHT (sLIGHT) triggers death of about 50% of purified embryonic motoneurons after 48 h of treatment (Supplementary Fig S1A) [5]. To determine whether LIGHT elicits axon outgrowth and branching in motoneurons, we added sLIGHT to motoneuron cultures for 24 h to avoid biased analysis due to the loss of differentially vulnerable populations of motoneurons after longer exposure to the ligand.…”

Section: Light Promotes Axon Outgrowth and Branching In Motoneuronsmentioning

confidence: 99%

“…LIGHT has been proposed to contribute to the selective degeneration of motoneurons in the fatal paralytic disorder amyotrophic lateral sclerosis (ALS) [5,6]. Astrocytes expressing an ALScausing mutation in the superoxide dismutase-1 (SOD1) gene are selectively toxic toward motoneurons [7].…”

Section: Introductionmentioning

confidence: 99%

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Somatic and axonal LIGHT signaling elicit degenerative and regenerative responses in motoneurons, respectively

et al. 2014

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A receptor-ligand interaction can evoke a broad range of biological activities in different cell types depending on receptor identity and cell type-specific post-receptor signaling intermediates. Here, we show that the TNF family member LIGHT, known to act as a deathtriggering factor in motoneurons through LT-bR, can also promote axon outgrowth and branching in motoneurons through the same receptor. LIGHT-induced axonal elongation and branching require ERK and caspase-9 pathways. This distinct response involves a compartment-specific activation of LIGHT signals, with somatic activation-inducing death, while axonal stimulation promotes axon elongation and branching in motoneurons. Following peripheral nerve damage, LIGHT increases at the lesion site through expression by invading B lymphocytes, and genetic deletion of Light significantly delays functional recovery. We propose that a central and peripheral activation of the LIGHT pathway elicits different functional responses in motoneurons.

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Section: Regional Activation Of Light-dependent Signaling Triggers Opmentioning

confidence: 53%

“…Motoneurons were isolated from embryonic day (E) 12.5 mice of indicated genotype as previously described [5]. Microfluidic devices were prepared as described in [10].…”

Section: Methodsmentioning

confidence: 99%

Section: Light Promotes Axon Outgrowth and Branching In Motoneuronsmentioning

confidence: 97%

Section: Light Promotes Axon Outgrowth and Branching In Motoneuronsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Somatic and axonal LIGHT signaling elicit degenerative and regenerative responses in motoneurons, respectively

et al. 2014

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

Hounoum

Mavel

Coque

et al. 2017

Glia

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The selective degeneration of motoneuron that typifies amyotrophic lateral sclerosis (ALS) implicates non-cell-autonomous effects of astrocytes. However, mechanisms underlying astrocyte-mediated neurotoxicity remain largely unknown. According to the determinant role of astrocyte metabolism in supporting neuronal function, we propose to explore the metabolic status of astrocytes exposed to ALS-associated conditions. We found a significant metabolic dysregulation including purine, pyrimidine, lysine, and glycerophospholipid metabolism pathways in astrocytes expressing an ALS-causing mutated superoxide dismutase-1 (SOD1) when co-cultured with motoneurons. SOD1 astrocytes exposed to glutamate revealed a significant modification of the astrocyte metabolic fingerprint. More importantly, we observed that SOD1 mutation and glutamate impact the cellular shuttling of lactate between astrocytes and motoneurons with a decreased in extra- and intra-cellular lactate levels in astrocytes. Based on the emergent strategy of metabolomics, this work provides novel insight for understanding metabolic dysfunction of astrocytes in ALS conditions and opens the perspective of therapeutics targets through focusing on these metabolic pathways. GLIA 2017 GLIA 2017;65:592-605.

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Mutant C9orf72 human iPSC‐derived astrocytes cause non‐cell autonomous motor neuron pathophysiology

Zhao

Devlin

Chouhan

et al. 2019

Glia

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Mutations in C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis (ALS). Accumulating evidence implicates astrocytes as important non‐cell autonomous contributors to ALS pathogenesis, although the potential deleterious effects of astrocytes on the function of motor neurons remains to be determined in a completely humanized model of C9orf72‐mediated ALS. Here, we use a human iPSC‐based model to study the cell autonomous and non‐autonomous consequences of mutant C9orf72 expression by astrocytes. We show that mutant astrocytes both recapitulate key aspects of C9orf72‐related ALS pathology and, upon co‐culture, cause motor neurons to undergo a progressive loss of action potential output due to decreases in the magnitude of voltage‐activated Na+ and K+ currents. Importantly, CRISPR/Cas‐9 mediated excision of the C9orf72 repeat expansion reverses these phenotypes, confirming that the C9orf72 mutation is responsible for both cell‐autonomous astrocyte pathology and non‐cell autonomous motor neuron pathophysiology.

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IFNγ triggers a LIGHT-dependent selective death of motoneurons contributing to the non-cell-autonomous effects of mutant SOD1

Cited by 71 publications

References 49 publications

Somatic and axonal LIGHT signaling elicit degenerative and regenerative responses in motoneurons, respectively

Somatic and axonal LIGHT signaling elicit degenerative and regenerative responses in motoneurons, respectively

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

Mutant C9orf72 human iPSC‐derived astrocytes cause non‐cell autonomous motor neuron pathophysiology

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