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