通过KA介导的兴奋毒性通过激活ferritinophagy诱导神经元铁亡
Yi-Yue Jiang1, Wei-Long Wu1, Jia-Ni Huang1
1Department of Pharmacology College of Pharmaceutical Sciences, Suzhou Key Laboratory of Aging and Nervous Diseases, and Jiangsu Key Laboratory of Neuropsychiatric Diseases, Soochow University, Suzhou, China.
CNS neuroscience & therapeutics
|September 22, 2024
概括
凯尼酸 (KA) 过载会触发神经元中的铁代谢和铁代谢,但准NCOA4或铁代谢可以防止神经元损伤. 这突出了刺激毒性的潜在治疗策略.
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
- 生物化学 生物化学
背景情况:
- 凯尼酸 (KA) 是一种强大的神经毒素,可诱导激发性毒性,这种过程与各种神经疾病有关.
- 铁过载越来越被认为是刺激毒性中神经元损伤的一个因素.
- 费里丁,选择性降解费里,在细胞铁平衡中起作用,可以导致铁的释放.
研究的目的:
- 调查Fe2+过载在KA诱导的兴奋毒性中的作用.
- 探索ferritinophagy选择性载荷受体NCOA4在激发性毒性的病变发生过程中的参与.
- 为了确定是否向费里丁法可以减轻KA诱导的神经元损伤.
主要方法:
- 在小鼠的KA注射后,西部涂抹以评估蛋白质表达 (FTH1,NCOA4,Lamp2,TfR,FPN,DMT1).
- 同焦点显微镜可视化Fe2+与 lysosomes 在初级皮质神经元中的同位素.
- 使用desferrioxamine (DFO) 干预铁化,CCK8测定细胞活力,以及FerroOrange用于Fe2+检测.
- 测量活性氧物种 (ROS) 和铁灭生物标志物PTGS2mRNA水平.
- 使用3-甲基氨酸 (3-MA) 抑制自,并通过lentivirus传染抑制NCOA4.
主要成果:
- KA显著上调NCOA4,DMT1和Lamp2,同时降低FTH1,表明铁代谢和溶酶体活性发生了变化.
- KA治疗增加了Fe2+与溶酶体的同位化,并提高了细胞内Fe2+水平.
- DFO治疗挽救了细胞活力,减少了脂质过氧化,降低了PTGS2表达,减轻了KA引起的损伤.
- 用3-MA抑制自,逆转了KA诱导的费里替诺和费洛.
- 在接受KA治疗的神经元中,NCOA4倒置显著改善了细胞活力,并降低了Fe2+水平.
结论:
- 由KA诱导的兴奋毒性激活了ferritinophagy,这是一个驱动下游ferroptosis的过程.
- 向ferritinophagy可以有效地抑制ferroptosis,并减轻KA诱导的神经元损伤.
- 与NCOA4的干扰为与兴奋毒性相关的疾病提供了一个有希望的治疗策略.
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