Signaling by cGAS–STING in Neurodegeneration, Neuroinflammation, and Aging

cGAS–STING, a component of the innate immune system, senses cytosolic DNA, which triggers an interferon-mediated response to clear pathogenic entities. cGAS–STING responds not only to foreign DNA from viruses and bacteria, but also to self-DNA, both mitochondrial and genomic, which enters the cytosol from senescent or dying cells. The pathway plays important roles in the brain and its activation is elicited predominantly by microglia, the resident macrophages of the brain to resolve inflammation. Excessive engagement of the cGAS–STING pathway in the brain can lead to neuroinflammation and neurodegeneration. Targeting of the cGAS–STING pathway may afford therapeutic benefits in aging and age-related neurodegenerative disorders. Recognition of foreign or misplaced nucleic acids is one of the principal modes by which the immune system detects pathogenic entities. When cytosolic DNA is sensed, a signal is relayed via the cGAS–STING pathway: this involves the activation of cyclic GMP-AMP (cGMP-AMP) synthase (cGAS) and generation of the cyclic dinucleotide cGAMP, followed by the induction of stimulator of interferon genes (STING). The cGAS–STING pathway responds to viral, bacterial, and self-DNA. Whereas it generally mediates immune surveillance and is often neuroprotective, excessive engagement of the system can be deleterious. This is relevant in aging and age-related neurological diseases, where neuroinflammation contributes to disease progression. This review focuses on cGAS–STING signaling in aging, neurodegeneration, and neuroinflammation, and on therapeutic implications. Recognition of foreign or misplaced nucleic acids is one of the principal modes by which the immune system detects pathogenic entities. When cytosolic DNA is sensed, a signal is relayed via the cGAS–STING pathway: this involves the activation of cyclic GMP-AMP (cGMP-AMP) synthase (cGAS) and generation of the cyclic dinucleotide cGAMP, followed by the induction of stimulator of interferon genes (STING). The cGAS–STING pathway responds to viral, bacterial, and self-DNA. Whereas it generally mediates immune surveillance and is often neuroprotective, excessive engagement of the system can be deleterious. This is relevant in aging and age-related neurological diseases, where neuroinflammation contributes to disease progression. This review focuses on cGAS–STING signaling in aging, neurodegeneration, and neuroinflammation, and on therapeutic implications. derived from the Greek word autophagos (self-devouring); refers to the process by which the body eliminates unwanted or damaged components. part of the forebrain and a central component of the motor and reward systems. also called the Golgi complex or the Golgi; an organelle that processes, sorts, and traffics proteins to their destinations. an arm of the immune system, the other being the adaptive immune system. The innate immune system is the first line of defense, which recognizes pathogenic entities and is activated immediately once a pathogen is detected. cytokines, molecules used for intercell communication, with antiviral and immunomodulatory effects. a type of stroke caused by blockage of the blood supply to the brain leading to neuronal death.