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<p>Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron loss, leading to paralysis and death. Mutations in the <i>fused in sarcoma</i> (<i>FUS</i>) gene cause early-onset ALS with rapid disease progression. Although motor neuron degeneration is central to ALS, recent studies highlight a significant role for dysfunctional glial cells, particularly astrocytes, in disease progression. In this study, we generated astrocytes from <i>FUS</i><sup><i>R521H</i></sup> mutant and isogenic human induced pluripotent stem cells (hiPSCs) by inducible overexpressing SOX9. Lipidomic analysis revealed marked glycerophospholipid deficiencies in <i>FUS</i><sup><i>R521H</i></sup> mutant astrocytes, especially reduced phosphatidylcholine (PC) and phosphatidylinositol (PI) levels. This reduction in PC was also observed in <i>FUS</i><sup><i>R521H</i></sup> mutant oligodendroglial progenitors and motor neurons, suggesting a potential dysregulation of glycerophospholipid metabolism across multiple central nervous system (CNS) cell types in <i>FUS</i>-ALS. These observations highlight the need for further investigation into lipid dysregulation and its relevance to <i>FUS</i>-ALS pathogenesis.</p>

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Altered Lipid Homeostasis in Mutant FUSR521H Astrocytes from HiPSCs

  • 期刊论文

  • 发表日期：

    2025年6月14日

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  • Yingli Zhu,
  • Katrien Neyrinck,
  • Thibaut Burg,
  • Yoke Chin Chai,
  • Fatemeharefeh Nami,
  • Karan Ahuja,
  • Johannes V. Swinnen,
  • Ludo Van Den Bosch,
  • Catherine Verfaillie

摘要

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron loss, leading to paralysis and death. Mutations in the fused in sarcoma (FUS) gene cause early-onset ALS with rapid disease progression. Although motor neuron degeneration is central to ALS, recent studies highlight a significant role for dysfunctional glial cells, particularly astrocytes, in disease progression. In this study, we generated astrocytes from FUSR521H mutant and isogenic human induced pluripotent stem cells (hiPSCs) by inducible overexpressing SOX9. Lipidomic analysis revealed marked glycerophospholipid deficiencies in FUSR521H mutant astrocytes, especially reduced phosphatidylcholine (PC) and phosphatidylinositol (PI) levels. This reduction in PC was also observed in FUSR521H mutant oligodendroglial progenitors and motor neurons, suggesting a potential dysregulation of glycerophospholipid metabolism across multiple central nervous system (CNS) cell types in FUS-ALS. These observations highlight the need for further investigation into lipid dysregulation and its relevance to FUS-ALS pathogenesis.