HERV-K (HML-2) 包膜蛋白诱导线粒体去极化和神经毒性通过内分泌体铁阻滞
Peter W Halcrow1, Darius N K Quansah1, Nirmal Kumar1
1Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota 58202.
概括
人体内源逆转录病毒 (HERVs) 蛋白HERV-K Env通过脱酸内溶酶体,释放铁和增加氧化应激来驱动ALS的神经退行. 这导致运动神经元细胞死亡,这一过程通过向CD98受体或铁来阻止.
科学领域:
- 神经科学是一个神经科学.
- 分子生物学分子生物学
- 细胞生物学 细胞生物学
背景情况:
- 肌缩侧面硬化症 (ALS) 涉及运动神经元退化,并与人体内源逆转录病毒 (HERVs) 相关.
- 在ALS患者中发现的HERV-K亚型HML-2包膜蛋白 (HERV-K Env) 通过CD98受体相互作用促进神经退行.
- 由铁 (Fe2+) 和活性氧物种 (ROS) 驱动的氧化应激是ALS病变的一个关键因素,内分泌体在铁调节中发挥着关键作用.
研究的目的:
- 为了研究HERV-K Env对内分泌体pH和铁水平的影响.
- 为了确定 HERV-K Env 诱导的神经毒性是否由内分泌体的铁释放介导.
- 阐明 HERV-K Env 促成 ALS 发病的机制.
主要方法:
- 使用了SH-SY5Y神经母细胞瘤细胞和人类皮质神经元 (HCNs).
- 通过CD98受体检查了HERV-K Env细胞内.
- 评估了内分泌体pH值,Fe2+度 (内分泌体,细胞体,线粒体),ROS水平和线粒体膜潜力.
- 研究了抗CD98受体抗体和deferoxamine (一种铁化剂) 对这些过程的影响.
- 监测细胞活力和细胞死亡.
主要成果:
- HERV-K Env通过CD98受体和度依赖脱酸的内分泌体进行了内细胞化.
- 内分泌体Fe2+水平下降,而细胞质和线粒体Fe2+和ROS水平增加.
- 线粒体膜潜力脱极化,导致细胞死亡.
- 这些效应被抗CD98受体抗体和deferoxamine所废除.
结论:
- HERV-K Env 细胞内会触发内酶体脱酸,随后Fe2+ 流入细胞质.
- 由HERV-K Env驱动的细胞和线粒体Fe2+和ROS水平增加,在ALS中机械导致神经毒性和细胞死亡.
- 针对HERV-K Env与CD98的相互作用或管理铁失调,为ALS提供了潜在的治疗策略.
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