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TDP-43通过mPTP触发线粒体DNA释放以激活ALS中的cGAS/STING

Chien-Hsiung Yu¹, Sophia Davidson¹, Cassandra R Harapas¹

¹Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia.

|October 8, 2020

概括

在ALS中细胞质TDP-43通过线粒体DNA释放和cGAS-STING激活触发炎症. 抑制这种途径可以减少神经炎症, 为ALS提供潜在的治疗点.

科学领域:

神经科学
免疫学
遗传学

背景情况:

细胞质TDP-43积累是肌缩侧面硬化症 (ALS) 的标志.
这种病理与涉及核因子 κB (NF-κB) 和I型干扰素 (IFN) 途径的神经炎症有关.

研究的目的:

研究细胞质DNA传感器循环氨酸单酸 (GMP) - AMP合成酶 (cGAS) 在ALS中TDP-43相关的神经炎症中的作用.
探索针对ALS的cGAS-STING途径的治疗潜力.

主要方法:

使用诱导多能干细胞 (iPSC) 衍生的运动神经元和TDP-43突变小鼠模型.
研究了cGAS和STING的药理抑制和遗传删除的影响.
测量了NF-κB和I型IFN通路的激活.
对ALS患者的脊髓样本进行了cGAS信号代谢物的分析.

主要成果:

线粒体的TDP-43入侵释放DNA,激活cGAS-STING通路.
在细胞和动物模型中,抑制或删除cGAS/ STING可以防止NF- kB和I型IFN的上调.
在ALS患者的脊髓中发现了cGAS代谢物cGAMP的升高水平.

结论:

线粒体DNA释放和随后的cGAS/STING激活是ALS中TDP-43相关病理的关键驱动因素.
在ALS治疗中,cGAS-STING路径是一个有前途的治疗点.

关键词:

美国国际金融基金在 NF-κB 一个一个TDP-43 cGAMP 在 cGAS 公司 mPTP 的使用情况线粒体神经退行症

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