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依赖DLK的轴突线粒体裂变驱动了轴突切割后的退化

Jorge Gómez-Deza¹, Matthew Nebiyou¹, Mor R Alkaslasi¹

¹Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.

Nature communications

|December 31, 2024

概括

研究人员开发了一个人类iPSC神经退行模型. 他们发现双氨酸拉链激酶 (DLK) 通过与胺相关的蛋白质1 (DRP1) 酸化启动了细胞亡波,导致神经元死亡.

科学领域:

神经科学是一个神经科学.
细胞生物学细胞生物学
遗传学是一个遗传学.

背景情况:

由于疾病模型不足,神经退行性疾病缺乏有效的治疗方法.
目前的模型无法准确地回顾人类神经元退化.

研究的目的:

开发一种可再生的人类诱导多能干细胞 (iPSC) 基模型,用于研究神经退行.
为了确定关键的分子机制驱动神经元细胞损伤后死亡.

主要方法:

激光轴切术用于诱导人类iPSC衍生的神经元的逆行轴突退化.
时间延迟共聚焦成像追踪了受伤后的细胞事件.
使用CRISPR-Cas9技术,消耗了与动氨酸相关的蛋白1 (DRP1).

主要成果:

激光轴切引发了从受伤部位到 soma 的线粒体裂变的亡波.
双氨酸拉链激酶 (DLK) 被确定为轴突中这种亡波的发起者.
线粒体分裂和细胞死亡取决于DLK介导的DRP1.1酸化.
通过CRISPR介导的DRP1枯竭保护了小鼠视网膜质神经元在视神经被压碎后的退化.

结论:

开发的人类iPSC模型为研究神经退行提供了一个平台.
通过DLK介导的DRP1酸化是损伤诱导的神经元亡的一个关键机制.
准DLK或DRP1可能为神经退行性疾病提供治疗策略.

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