Mechanism and therapeutic potential of targeting cGAS-STING signaling in neurological disorders.

TitleMechanism and therapeutic potential of targeting cGAS-STING signaling in neurological disorders.
Publication TypeJournal Article
Year of Publication2023
AuthorsHuang Y, Liu B, Sinha SC, Amin S, Gan L
JournalMol Neurodegener
Date Published2023 Nov 08
KeywordsDNA, Humans, Interferon Type I, Nervous System Diseases, Nucleotidyltransferases, Signal Transduction

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.

Alternate JournalMol Neurodegener
PubMed ID37941028
PubMed Central IDPMC10634099
Grant ListR01AG072758 / AG / NIA NIH HHS / United States
R01AG054214 / AG / NIA NIH HHS / United States
R01AG074541 / AG / NIA NIH HHS / United States