Zhu Yingli, Neyrinck Katrien, Burg Thibaut, Chai Yoke Chin, Nami Fatemeharefeh, Ahuja Karan, Swinnen Johannes V, Van Den Bosch Ludo, Verfaillie Catherine
Department of Development and Regeneration, Stem Cell Institute, KU Leuven, 3000, Louvain, Belgium.
KU Leuven, Department of Neurosciences, Experimental Neurology and Leuven Brain Institute (LBI), 3000, Leuven, Belgium.
Mol Neurobiol. 2025 Jun 14. doi: 10.1007/s12035-025-05127-6.
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.
肌萎缩侧索硬化症（ALS）是一种进行性神经退行性疾病，其特征是运动神经元丧失，最终导致瘫痪和死亡。肉瘤融合（FUS）基因突变会导致早发性ALS，并伴有疾病的快速进展。尽管运动神经元变性是ALS的核心，但最近的研究强调了功能失调的神经胶质细胞，尤其是星形胶质细胞，在疾病进展中的重要作用。在本研究中，我们通过诱导过表达SOX9，从FUS突变体和同基因人类诱导多能干细胞（hiPSC）中生成了星形胶质细胞。脂质组学分析显示，FUS突变体星形胶质细胞中存在明显的甘油磷脂缺乏，尤其是磷脂酰胆碱（PC）和磷脂酰肌醇（PI）水平降低。在FUS突变体少突胶质前体细胞和运动神经元中也观察到了PC的这种降低，这表明在FUS-ALS中，多种中枢神经系统（CNS）细胞类型的甘油磷脂代谢可能存在失调。这些观察结果凸显了进一步研究脂质失调及其与FUS-ALS发病机制相关性的必要性。
