Cytoplasmic accumulation of TDP-43 is a disease hallmark for many cases of amyotrophic lateral sclerosis (ALS), associated with a neuroinflammatory cytokine profile related to upregulation of nuclear factor κB (NF-κB) and type I interferon (IFN) pathways. Here we show that this inflammation is driven by the cytoplasmic DNA sensor cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS) when TDP-43 invades mitochondria and releases DNA via the permeability transition pore. Pharmacologic inhibition or genetic deletion of cGAS and its downstream signaling partner STING prevents upregulation of NF-κB and type I IFN induced by TDP-43 in induced pluripotent stem cell (iPSC)-derived motor neurons and in TDP-43 mutant mice. Finally, we document elevated levels of the specific cGAS signaling metabolite cGAMP in spinal cord samples from patients, which may be a biomarker of mtDNA release and cGAS/STING activation in ALS. Our results identify mtDNA release and cGAS/STING activation as critical determinants of TDP-43-associated pathology and demonstrate the potential for targeting this pathway in ALS.

TDP-43 的细胞质积累是许多肌萎缩侧索硬化症 (ALS) 病例的疾病标志，与与核因子 κB (NF-κB) 和 I 型干扰素 (IFN) 通路上调相关的神经炎性细胞因子谱相关。在这里，我们表明当 TDP-43 侵入线粒体并通过通透性转换孔释放 DNA 时，这种炎症是由细胞质 DNA 传感器环磷酸鸟苷 (GMP)-AMP 合酶 (cGAS) 驱动的。cGAS 及其下游信号伙伴 STING 的药理学抑制或基因缺失可防止 TDP-43 在诱导多能干细胞 (iPSC) 衍生的运动神经元和 TDP-43 突变小鼠中诱导的 NF-κB 和 I 型 IFN 上调。最后，我们记录了患者脊髓样本中特定 cGAS 信号代谢物 cGAMP 水平升高，这可能是 ALS 中 mtDNA 释放和 cGAS/STING 激活的生物标志物。我们的结果将 mtDNA 释放和 cGAS/STING 激活确定为 TDP-43 相关病理学的关键决定因素，并证明了在 ALS 中靶向该途径的潜力。