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TNFα prevents FGF4-mediated rescue of astrocyte dysfunction and reactivity in human ALS models

Velasquez, Erika LU ; Savchenko, Ekaterina LU ; Marmolejo-Martínez-Artesero, Sara ; Challuau, Désiré ; Aebi, Aline ; Pomeshchik, Yuriy LU orcid ; Lamas, Nuno Jorge LU ; Vihinen, Mauno LU orcid ; Rezeli, Melinda LU orcid and Schneider, Bernard , et al. (2024) In Neurobiology of Disease 201.
Abstract

Astrocytes play a crucial role in the onset and progression of amyotrophic lateral sclerosis (ALS), a fatal disorder marked by the degeneration of motor neurons (MNs) in the central nervous system. Although astrocytes in ALS are known to be toxic to MNs, the pathological changes leading to their neurotoxic phenotype remain poorly understood. In this study, we generated human astrocytes from induced pluripotent stem cells (iPSCs) carrying the ALS-associated A4V mutation in superoxide dismutase 1 (SOD1) to examine early cellular pathways and network changes. Proteomic analysis revealed that ALS astrocytes are both dysfunctional and reactive compared to control astrocytes. We identified significant alterations in the levels of proteins... (More)

Astrocytes play a crucial role in the onset and progression of amyotrophic lateral sclerosis (ALS), a fatal disorder marked by the degeneration of motor neurons (MNs) in the central nervous system. Although astrocytes in ALS are known to be toxic to MNs, the pathological changes leading to their neurotoxic phenotype remain poorly understood. In this study, we generated human astrocytes from induced pluripotent stem cells (iPSCs) carrying the ALS-associated A4V mutation in superoxide dismutase 1 (SOD1) to examine early cellular pathways and network changes. Proteomic analysis revealed that ALS astrocytes are both dysfunctional and reactive compared to control astrocytes. We identified significant alterations in the levels of proteins linked to ALS pathology and the innate immune cGAS-STING pathway. Furthermore, we found that ALS astrocyte reactivity differs from that of control astrocytes treated with tumor necrosis factor alpha (TNFα), a key cytokine in inflammatory reactions. We then evaluated the potential of fibroblast growth factor (FGF) 2, 4, 16, and 18 to reverse ALS astrocyte phenotype. Among these, FGF4 successfully reversed ALS astrocyte dysfunction and reactivity in vitro. When delivered to the spinal cord of the SOD1G93A mouse model of ALS, FGF4 lowered astrocyte reactivity. However, this was not sufficient to protect MNs from cell death. Further analysis indicated that TNFα abrogated the reactivity reduction achieved by FGF4, suggesting that complete rescue of the ALS phenotype by FGF4 is hindered by ongoing complex neuroinflammatory processes in vivo. In summary, our data demonstrate that astrocytes generated from ALS iPSCs are inherently dysfunctional and exhibit an immune reactive phenotype. Effectively targeting astrocyte dysfunction and reactivity in vivo may help mitigate ALS and prevent MN death.

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type
Contribution to journal
publication status
published
subject
keywords
Astrocytes/metabolism, Amyotrophic Lateral Sclerosis/metabolism, Humans, Animals, Mice, Tumor Necrosis Factor-alpha/metabolism, Fibroblast Growth Factor 4/metabolism, Induced Pluripotent Stem Cells/metabolism, Superoxide Dismutase-1/genetics, Mice, Transgenic, Disease Models, Animal, Motor Neurons/metabolism, Spinal Cord/metabolism
in
Neurobiology of Disease
volume
201
article number
106687
publisher
Academic Press
external identifiers
  • scopus:85205452087
  • pmid:39362568
ISSN
0969-9961
DOI
10.1016/j.nbd.2024.106687
language
English
LU publication?
yes
additional info
Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.
id
6aecb10e-255a-4770-a5ba-5a1a179cea2a
date added to LUP
2026-03-19 10:44:05
date last changed
2026-03-20 04:01:34
@article{6aecb10e-255a-4770-a5ba-5a1a179cea2a,
  abstract     = {{<p>Astrocytes play a crucial role in the onset and progression of amyotrophic lateral sclerosis (ALS), a fatal disorder marked by the degeneration of motor neurons (MNs) in the central nervous system. Although astrocytes in ALS are known to be toxic to MNs, the pathological changes leading to their neurotoxic phenotype remain poorly understood. In this study, we generated human astrocytes from induced pluripotent stem cells (iPSCs) carrying the ALS-associated A4V mutation in superoxide dismutase 1 (SOD1) to examine early cellular pathways and network changes. Proteomic analysis revealed that ALS astrocytes are both dysfunctional and reactive compared to control astrocytes. We identified significant alterations in the levels of proteins linked to ALS pathology and the innate immune cGAS-STING pathway. Furthermore, we found that ALS astrocyte reactivity differs from that of control astrocytes treated with tumor necrosis factor alpha (TNFα), a key cytokine in inflammatory reactions. We then evaluated the potential of fibroblast growth factor (FGF) 2, 4, 16, and 18 to reverse ALS astrocyte phenotype. Among these, FGF4 successfully reversed ALS astrocyte dysfunction and reactivity in vitro. When delivered to the spinal cord of the SOD1G93A mouse model of ALS, FGF4 lowered astrocyte reactivity. However, this was not sufficient to protect MNs from cell death. Further analysis indicated that TNFα abrogated the reactivity reduction achieved by FGF4, suggesting that complete rescue of the ALS phenotype by FGF4 is hindered by ongoing complex neuroinflammatory processes in vivo. In summary, our data demonstrate that astrocytes generated from ALS iPSCs are inherently dysfunctional and exhibit an immune reactive phenotype. Effectively targeting astrocyte dysfunction and reactivity in vivo may help mitigate ALS and prevent MN death.</p>}},
  author       = {{Velasquez, Erika and Savchenko, Ekaterina and Marmolejo-Martínez-Artesero, Sara and Challuau, Désiré and Aebi, Aline and Pomeshchik, Yuriy and Lamas, Nuno Jorge and Vihinen, Mauno and Rezeli, Melinda and Schneider, Bernard and Raoul, Cedric and Roybon, Laurent}},
  issn         = {{0969-9961}},
  keywords     = {{Astrocytes/metabolism; Amyotrophic Lateral Sclerosis/metabolism; Humans; Animals; Mice; Tumor Necrosis Factor-alpha/metabolism; Fibroblast Growth Factor 4/metabolism; Induced Pluripotent Stem Cells/metabolism; Superoxide Dismutase-1/genetics; Mice, Transgenic; Disease Models, Animal; Motor Neurons/metabolism; Spinal Cord/metabolism}},
  language     = {{eng}},
  month        = {{10}},
  publisher    = {{Academic Press}},
  series       = {{Neurobiology of Disease}},
  title        = {{TNFα prevents FGF4-mediated rescue of astrocyte dysfunction and reactivity in human ALS models}},
  url          = {{http://dx.doi.org/10.1016/j.nbd.2024.106687}},
  doi          = {{10.1016/j.nbd.2024.106687}},
  volume       = {{201}},
  year         = {{2024}},
}