Department of Biological Sciences, St. John's University, New York City, New York, USA.
FEBS Open Bio. 2023 Mar;13(3):419-433. doi: 10.1002/2211-5463.13545. Epub 2023 Jan 24.
Ferroptosis is a regulated form of cell death driven by the lethal accumulation of lipid peroxides in cell membranes. Several regulators of ferroptosis have been identified using cancer cell lines. However, the cellular pathways of ferroptosis in neurons remain poorly characterized. In this study, we used a mouse embryonic stem cell-derived motor neuron model to investigate how motor neurons respond to ferroptosis inducers. Pharmacological and genetic inhibition of glutathione peroxidase 4 (GPx4) induced ferroptosis in motor neurons, while system x inhibition by erastin had no effect. RNA-seq analysis showed that the expression levels of several genes were altered during RSL3-induced ferroptosis. Subsequent bioinformatic analysis revealed alterations in several biological pathways during ferroptosis, including synaptogenesis and calcium signaling. Finally, we found that edaravone, an FDA-approved drug for treating amyotrophic lateral sclerosis (ALS) disease, rescued motor neurons from RSL3-induced ferroptosis. Our data highlight the crucial role of GPx4 in ferroptosis regulation and demonstrate that stem cell-derived motor neuron culture is a valuable model to study ferroptosis at the single-cell level in a neuronal context.
铁死亡是一种受细胞膜中脂质过氧化物累积驱动的受调控的细胞死亡形式。已经使用癌细胞系鉴定了几种铁死亡调节剂。然而，神经元中的铁死亡细胞途径仍未得到很好的描述。在这项研究中，我们使用源自小鼠胚胎干细胞的运动神经元模型来研究运动神经元如何对铁死亡诱导剂做出反应。谷胱甘肽过氧化物酶 4 (GPx4) 的药理学和遗传学抑制诱导了运动神经元中的铁死亡，而 erastin 对系统 x 的抑制则没有作用。RNA-seq 分析表明，在 RSL3 诱导的铁死亡过程中，几个基因的表达水平发生了改变。随后的生物信息学分析显示，在铁死亡过程中，包括突触发生和钙信号在内的几个生物学途径发生了改变。最后，我们发现，已获美国食品药品监督管理局（FDA）批准用于治疗肌萎缩侧索硬化症（ALS）疾病的依达拉奉可挽救 RSL3 诱导的铁死亡中的运动神经元。我们的数据强调了 GPx4 在铁死亡调节中的关键作用，并表明源自干细胞的运动神经元培养物是在神经元背景下研究铁死亡的单细胞水平的有价值模型。
