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小胶质细胞铁死亡受SEC24B调控并促进神经退行性的发生
作者:小柯机器人 发布时间:2022/12/20 19:17:28

美国赛诺菲公司Timothy R. Hammond研究小组发现,小胶质细胞铁死亡受SEC24B调控并促进神经退行性的发生。这一研究成果于2022年12月19日在线发表在国际学术期刊《自然—神经科学》上。

研究人员展示了在三培养系统中生长的人诱导多能干细胞衍生的小胶质细胞对铁高度敏感,易受铁死亡(一种依赖铁的细胞死亡形式)的影响。此外,铁过载导致小胶质细胞转录状态的显著转变,与在帕金森病(PD)死后脑小胶质细胞中发现的转录组特征重叠。数据还表明,这种小胶质细胞反应有助于神经退行性变,因为从三培养系统中去除小胶质细胞大大延迟了铁诱导的神经毒性。为了阐明调节小胶质细胞铁反应的机制,研究人员进行了全基因组CRISPR筛选,并确定了新的铁死亡调控因子,包括囊泡转运基因SEC24B。这些数据表明,小胶质细胞铁过载和铁死亡在神经退行性变中起着关键作用。

据介绍,铁调节异常与多种神经退行性疾病有关,包括PD。铁负载的小胶质细胞经常在受影响的大脑区域被发现,但铁的积累如何影响小胶质细胞生理并导致神经退行性变尚不清楚。

附:英文原文

Title: Microglia ferroptosis is regulated by SEC24B and contributes to neurodegeneration

Author: Ryan, Sean K., Zelic, Matija, Han, Yingnan, Teeple, Erin, Chen, Luoman, Sadeghi, Mahdiar, Shankara, Srinivas, Guo, Lilu, Li, Cong, Pontarelli, Fabrizio, Jensen, Elizabeth H., Comer, Ashley L., Kumar, Dinesh, Zhang, Mindy, Gans, Joseph, Zhang, Bailin, Proto, Jonathan D., Saleh, Jacqueline, Dodge, James C., Savova, Virginia, Rajpal, Deepak, Ofengeim, Dimitry, Hammond, Timothy R.

Issue&Volume: 2022-12-19

Abstract: Iron dysregulation has been implicated in multiple neurodegenerative diseases, including Parkinson’s disease (PD). Iron-loaded microglia are frequently found in affected brain regions, but how iron accumulation influences microglia physiology and contributes to neurodegeneration is poorly understood. Here we show that human induced pluripotent stem cell-derived microglia grown in a tri-culture system are highly responsive to iron and susceptible to ferroptosis, an iron-dependent form of cell death. Furthermore, iron overload causes a marked shift in the microglial transcriptional state that overlaps with a transcriptomic signature found in PD postmortem brain microglia. Our data also show that this microglial response contributes to neurodegeneration, as removal of microglia from the tri-culture system substantially delayed iron-induced neurotoxicity. To elucidate the mechanisms regulating iron response in microglia, we performed a genome-wide CRISPR screen and identified novel regulators of ferroptosis, including the vesicle trafficking gene SEC24B. These data suggest a critical role for microglia iron overload and ferroptosis in neurodegeneration.

DOI: 10.1038/s41593-022-01221-3

Source: https://www.nature.com/articles/s41593-022-01221-3

期刊信息

Nature Neuroscience:《自然—神经科学》,创刊于1998年。隶属于施普林格·自然出版集团,最新IF:21.126
官方网址:https://www.nature.com/neuro/
投稿链接:https://mts-nn.nature.com/cgi-bin/main.plex