内部收益率3
神经炎症
旁观者效应
细胞生物学
SOD1
干扰素
生物
线粒体
胞浆
化学
免疫学
先天免疫系统
免疫系统
炎症
基因
遗传学
生物化学
突变体
酶
作者
Hong Yien Tan,Yean K. Yong,Yuan Chao Xue,Huitao Liu,Tomomi Furihata,Esaki M. Shankar,Chen Seng Ng
出处
期刊:iScience
[Elsevier]
日期:2022-05-13
卷期号:25 (6): 104404-104404
被引量:27
标识
DOI:10.1016/j.isci.2022.104404
摘要
Neuroinflammation exacerbates the progression of SOD1-driven amyotrophic lateral sclerosis (ALS), although the underlying mechanisms remain largely unknown. Herein, we demonstrate that misfolded SOD1 (SOD1Mut)-causing ALS results in mitochondrial damage, thus triggering the release of mtDNA and an RNA:DNA hybrid into the cytosol in an mPTP-independent manner to activate IRF3- and IFNAR-dependent type I interferon (IFN-I) and interferon-stimulating genes. The neuronal hyper-IFN-I and pro-inflammatory responses triggered in ALS-SOD1Mut were sufficiently robust to cause a strong physiological outcome in vitro and in vivo. cGAS/DDX41-STING-signaling is amplified in bystander cells through inter-neuronal gap junctions. Our results highlight the importance of a common DNA-sensing pathway between SOD1 and TDP-43 in influencing the progression of ALS.
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