Altered Lipid Homeostasis in Mutant FUS^R521H Astrocytes from HiPSCs

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 FUS^R521H mutant and isogenic human induced pluripotent stem cells (hiPSCs) by inducible overexpressing SOX9. Lipidomic analysis revealed marked glycerophospholipid deficiencies in FUS^R521H mutant astrocytes, especially reduced phosphatidylcholine (PC) and phosphatidylinositol (PI) levels. This reduction in PC was also observed in FUS^R521H 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.