cGAS-STING targeting offers novel therapeutic opportunities in neurological diseases

Abstract

Cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) (cGAMP) synthase (cGAS) is a cytosolic DNA sensor that produces the secondary messenger cGAMP. cGAMP activates the endoplasmic reticulum-associated adaptor stimulator of interferon genes (STING) and activates the innate immune system to produce a type I interferon response. Besides sensing microbial DNA, cGAS can also be activated by self-DNA or endogenous DNA, including that derived from genotoxic extranuclear chromatin and mitochondrially released DNA, indicating that cGAS-STING is an important mechanism in sterile inflammatory responses, autoimmunity, and cellular senescence. However, aberrant activation of the cGAS-STING pathway results in inflammatory and autoimmune diseases. cGAS-STING has emerged as a vital mechanism driving the pathogenesis of inflammation, implicating cGAS-STING signaling in neurological diseases. In this review, we first outline the principal elements of the cGAS-STING signaling cascade, summarizing recent research highlighting how cGAS-STING activation contributes to the pathogenesis of neurological diseases, including various autoimmune, autoinflammatory, and neurodegenerative diseases. Next, we outline selective small-molecule modulators that function as cGAS-STING inhibitors and summarize their mechanisms for treating multiple neurological diseases. Finally, we discuss key limitations of the current therapeutic paradigm and generate possible strategies to overcome them.