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

Abstract

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.

Keywords: Autophagy; Environmental pollution; Heavy metal; Manganese; cGAS–STING pathway.