DNA sensing is a pivotal component of the innate immune system that is responsible for detecting mislocalized DNA and triggering downstream inflammatory pathways. Among the DNA sensors, cyclic GMP-AMP synthase (cGAS) is a primary player in detecting cytosolic DNA, including foreign DNA from pathogens and self-DNA released during cellular damage, culminating in a type I interferon (IFN-I) response through stimulator of interferon genes (STING) activation. IFN-I cytokines are essential in mediating neuroinflammation, which is widely observed in CNS injury, neurodegeneration, and aging, suggesting an upstream role for the cGAS DNA sensing pathway. In this review, we summarize the latest developments on the cGAS-STING DNA-driven immune response in various neurological diseases and conditions. Our review covers the current understanding of the molecular mechanisms of cGAS activation and highlights cGAS-STING signaling in various cell types of central and peripheral nervous systems, such as resident brain immune cells, neurons, and glial cells. We then discuss the role of cGAS-STING signaling in different neurodegenerative conditions, including tauopathies, Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis, as well as aging and senescence. Finally, we lay out the current advancements in research and development of cGAS inhibitors and assess the prospects of targeting cGAS and STING as therapeutic strategies for a wide spectrum of neurological diseases.

中文翻译：

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神经系统疾病中靶向 cGAS-STING 信号传导的机制和治疗潜力

DNA 传感是先天免疫系统的关键组成部分，负责检测错误定位的 DNA 并触发下游炎症通路。在 DNA 传感器中，环 GMP-AMP 合酶 (cGAS) 是检测胞质 DNA 的主要参与者，包括来自病原体的外源 DNA 和细胞损伤过程中释放的自身 DNA，最终通过刺激器产生 I 型干扰素 (IFN-I) 反应干扰素基因（STING）激活。IFN-I 细胞因子对于介导神经炎症至关重要，神经炎症在 CNS 损伤、神经退行性变和衰老中广泛观察到，表明 cGAS DNA 传感途径的上游作用。在这篇综述中，我们总结了 cGAS-STING DNA 驱动的免疫反应在各种神经系统疾病和病症中的最新进展。我们的综述涵盖了当前对 cGAS 激活分子机制的理解，并重点介绍了中枢和周围神经系统各种细胞类型（例如常驻脑免疫细胞、神经元和神经胶质细胞）中的 cGAS-STING 信号传导。然后，我们讨论了 cGAS-STING 信号在不同神经退行性疾病中的作用，包括 tau 蛋白病、阿尔茨海默病、帕金森病和肌萎缩侧索硬化症，以及衰老和衰老。最后，我们列出了当前 cGAS 抑制剂的研究和开发进展，并评估了以 cGAS 和 STING 为靶点作为多种神经系统疾病治疗策略的前景。