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以C9orf72扩张的患者衍生诱导多能干细胞作为研究前性痴呆病理学的模型

Sonia Infante-Tadeo¹, Diane L Barber¹

¹Department of Cell and Tissue Biology, University of California San Francisco, San Francisco, CA 94941.

Molecular biology of the cell

|October 8, 2025

概括

来自患者的诱导多能干细胞 (iPSC) 显示出前性痴呆症 (FTD) 的特征,而没有神经元差异化. lysosome 功能障碍与此有关,iPSCs 为FTD研究和药物发现提供了一个新的模型.

科学领域:

神经科学是一个神经科学.
遗传学是一个遗传学.
细胞生物学细胞生物学

背景情况:

前性痴呆症 (FTD) 与C9orf72重复扩张有关.
现有的FTD模型如脑活检和分化神经元都有局限性.
目前尚不清楚C9orf72的确切功能及其扩张的致病机制.

研究的目的:

在患者衍生诱导多能干细胞 (iPSCs) 中研究FTD的细胞特征.
探索 lysosome 功能障碍在 FTD 病变发生过程中的作用.
为了确定新的治疗点,并完善FTD建模.

主要方法:

对FTD特征的患者衍生的iPSCs的分析.
评估溶酶体功能 (pH,甲素活性).
RNA测序 (RNA-seq) 用于识别失调的转录和蛋白质表达分析.

主要成果:

不分化的FTD iPSCs表现出FTD的特征:升高的溶酶体pH,降低的甲素活性,TDP-43蛋白质病变和增加的核TFEB.
在FTD iPSC中降低 lysosome pH 改善了 TDP-43 蛋白质病变,突出了 lysosome 功能障碍.
RNA-seq确定了信号传导,细胞死亡和神经元发育途径中的失调基因,证实了新型FTD相关基因的蛋白质表达变化.

结论:

来自患者的iPSC可以作为研究FTD细胞病理学的宝贵模型.
lysosome 功能障碍是C9orf72介导的FTD的一个关键因素.
FTD iPSCs可用于药物查和治疗开发.

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