Department of Toxicology, School of Public Health, Lanzhou University, Lanzhou, Gansu, China.
Department of Toxicology, School of Public Health, Lanzhou University, Lanzhou, Gansu, China.
Environ Pollut. 2022 Dec 15;315:120412. doi: 10.1016/j.envpol.2022.120412. Epub 2022 Oct 12.
Chronic high-level heavy metal exposure increases the risk of developing different neurodegenerative diseases. Chronic excessive manganese (Mn) exposure is known to lead to neurodegenerative diseases. In addition, some evidence suggests that autophagy dysfunction plays an important role in the pathogenesis of various neurodegenerative diseases. Over the past decade, the DNA-sensing receptor cyclic GMP-AMP synthase (cGAS) and its downstream signal-efficient interferon gene stimulator (STING), as well as the molecular composition and regulatory mechanisms of this pathway have been well understood. The cGAS-STING pathway has emerged as a crucial mechanism to induce effective innate immune responses by inducing type I interferons in mammalian cells. Moreover, recent studies have found that Mn is the second activator of the cGAS-STING pathway besides dsDNA, and inducing autophagy is a primitive function for the activation of the cGAS-STING pathway. However, overactivation of the immune response can lead to tissue damage. This review discusses the mechanism of neurotoxicity induced by Mn exposure from the cGAS-STING-autophagy pathway. Future work exploiting the cGAS-STING-autophagy pathway may provide a novel perspective for manganese neurotoxicity.
慢性高水平重金属暴露增加了罹患不同神经退行性疾病的风险。众所周知，慢性过量锰（Mn）暴露可导致神经退行性疾病。此外，有证据表明，自噬功能障碍在各种神经退行性疾病的发病机制中发挥重要作用。在过去十年中，DNA 感应受体环鸟苷酸-腺苷酸合酶（cGAS）及其下游信号有效的干扰素基因刺激物（STING），以及该途径的分子组成和调节机制已得到充分理解。cGAS-STING 途径已成为通过在哺乳动物细胞中诱导 I 型干扰素来诱导有效先天免疫反应的关键机制。此外，最近的研究发现，Mn 是除 dsDNA 之外第二种激活 cGAS-STING 途径的物质，诱导自噬是激活 cGAS-STING 途径的原始功能。然而，过度激活免疫反应会导致组织损伤。本综述从 cGAS-STING-自噬途径讨论了 Mn 暴露引起的神经毒性的机制。未来利用 cGAS-STING-自噬途径的工作可能为锰神经毒性提供新的视角。
