The cGAS-STING-autophagy pathway: Novel perspectives in neurotoxicity induced by manganese exposure

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 Mn2+ 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.

Automated summary

Chronic high-level heavy metal exposure, especially excessive manganese (Mn) exposure, is known to increase the risk of developing neurodegenerative diseases. Autophagy dysfunction has been implicated in the pathogenesis of these diseases. The cGAS-STING pathway, which induces type I interferons in mammalian cells, has been well-studied and found to play a crucial role in effective innate immune responses. Recent research has also identified Mn2+ as an activator of this pathway, along with dsDNA, and autophagy has been identified as a primitive function for its activation. However, overactivation of the immune response can lead to tissue damage. Exploring the cGAS-STING-autophagy pathway may offer a new perspective on manganese neurotoxicity.