生物
细胞生物学
神经退行性变
诱导多能干细胞
突变体
内质网
遗传学
基因
病理
医学
胚胎干细胞
疾病
作者
Yin Zhu,Thibaut Burg,Katrien Neyrinck,Tim Vervliet,Fatemeharefeh Nami,Ellen Vervoort,Karan Ahuja,Maria Livia Sassano,Yoke Chin Chai,Arun Kumar Tharkeshwar,Jonathan De Smedt,Haibo Hu,Geert Bultynck,Patrizia Agostinis,Johannes V. Swinnen,Ludo Van Den Bosch,Rosa Maria Esteves Moreira da Costa,Cathérine Verfaillie
标识
DOI:10.1007/s00401-023-02666-x
摘要
Abstract Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative disorder, characterized by selective loss of motor neurons (MNs). A number of causative genetic mutations underlie the disease, including mutations in the fused in sarcoma ( FUS ) gene, which can lead to both juvenile and late-onset ALS. Although ALS results from MN death, there is evidence that dysfunctional glial cells, including oligodendroglia, contribute to neurodegeneration. Here, we used human induced pluripotent stem cells (hiPSCs) with a R521H or a P525L mutation in FUS and their isogenic controls to generate oligodendrocyte progenitor cells (OPCs) by inducing SOX10 expression from a TET-On SOX10 cassette. Mutant and control iPSCs differentiated efficiently into OPCs. RNA sequencing identified a myelin sheath-related phenotype in mutant OPCs. Lipidomic studies demonstrated defects in myelin-related lipids, with a reduction of glycerophospholipids in mutant OPCs. Interestingly, FUS R521H OPCs displayed a decrease in the phosphatidylcholine/phosphatidylethanolamine ratio, known to be associated with maintaining membrane integrity. A proximity ligation assay further indicated that mitochondria-associated endoplasmic reticulum membranes (MAM) were diminished in both mutant FUS OPCs. Moreover, both mutant FUS OPCs displayed increased susceptibility to ER stress when exposed to thapsigargin, and exhibited impaired mitochondrial respiration and reduced Ca 2+ signaling from ER Ca 2+ stores. Taken together, these results demonstrate a pathological role of mutant FUS in OPCs, causing defects in lipid metabolism associated with MAM disruption manifested by impaired mitochondrial metabolism with increased susceptibility to ER stress and with suppressed physiological Ca 2+ signaling. As such, further exploration of the role of oligodendrocyte dysfunction in the demise of MNs is crucial and will provide new insights into the complex cellular mechanisms underlying ALS.
科研通智能强力驱动
Strongly Powered by AbleSci AI