Liu Zhuhe, Bai Yunmeng, Xu Bingtian, Wen Haixia, Chen Kechun, Lin Jingfang, Wang Yuanyuan, Xu Jiangping, Wang Haitao, Shi Fudong, Wang Jigang, Wang Honghao
Department of Neurology, Center for Medical Research on Innovation and Translation, Institute of Clinical Medicine, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China.
Department of Nephrology, Shenzhen Key Laboratory of Kidney Diseases, The First Affiliated Hospital, School of Medicine, Shenzhen People's Hospital, Southern University of Science and Technology, Shenzhen, China.
J Neuroinflammation. 2025 Jan 22;22(1):14. doi: 10.1186/s12974-025-03348-z.
Abnormality in transactivating response region DNA binding protein 43 (TDP43) is well-recognized as the pathological hallmark of neurodegenerative diseases. However, the role of TDP43 in neuromyelitis optica spectrum disorder (NMOSD) remains unknown. Here, our observations demonstrate an upregulation of TDP43 in both in vitro and in vivo models of NMOSD, as well as in biological samples from NMOSD patients. Single-nucleus RNA sequencing revealed that NMOSD induced A1-like reactive astrocytes and astrocyte mitochondrial dysfunction in mice. We further found that NMOSD provoked the translocation of TDP43 to mitochondria and the release of mitochondrial DNA (mtDNA) into the cytoplasm. NMOSD caused activation of mtDNA/cyclic GMP-AMP synthase (cGAS) / stimulator of interferon genes (STING) pathway and A1-type inflammatory activation in astrocytes. Crucially, the knockdown of TDP43 markedly ameliorated NMOSD-induced mitochondrial dysfunction and the activation of the cGAS/STING pathway in astrocytes. Conversely, overexpression of TDP43 exacerbated these pathological changes. Specific silencing astrocytic TDP43 ameliorated NMOSD-induced injury in mice, and conversely, TDP43 overexpression intensified the injury. Meanwhile, both cGAS and STING inhibitors attenuated NMOSD-induced injury in mice. In summary, our data suggest that TDP43 exacerbates inflammatory activation of astrocytes in NMOSD through upregulating the mtDNA/cGAS/STING signaling pathway. Therefore, targeting TDP43 represents a compelling therapeutic strategy for NMOSD.
转录激活反应区DNA结合蛋白43（TDP43）异常是神经退行性疾病公认的病理标志。然而，TDP43在视神经脊髓炎谱系障碍（NMOSD）中的作用仍不清楚。在此，我们的观察结果表明，在NMOSD的体外和体内模型以及NMOSD患者的生物样本中，TDP43均上调。单核RNA测序显示，NMOSD可诱导小鼠产生A1样反应性星形胶质细胞和星形胶质细胞线粒体功能障碍。我们进一步发现，NMOSD可促使TDP43转位至线粒体，并使线粒体DNA（mtDNA）释放到细胞质中。NMOSD可导致mtDNA/环磷酸鸟苷-腺苷酸合酶（cGAS）/干扰素基因刺激因子（STING）通路激活以及星形胶质细胞A1型炎症激活。至关重要的是，敲低TDP43可显著改善NMOSD诱导的线粒体功能障碍以及星形胶质细胞中cGAS/STING通路的激活。相反，过表达TDP43会加剧这些病理变化。特异性沉默星形胶质细胞中的TDP43可改善NMOSD诱导的小鼠损伤，相反，TDP43过表达会加重损伤。同时，cGAS和STING抑制剂均可减轻NMOSD诱导的小鼠损伤。总之，我们的数据表明，TDP43通过上调mtDNA/cGAS/STING信号通路加剧NMOSD中星形胶质细胞的炎症激活。因此，靶向TDP43是一种有吸引力的NMOSD治疗策略。
