From protector to perpetrator: The cGAS-STING pathway at the intersection of neurodegeneration and neuroinflammation

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, a cornerstone of the innate immune system designed to combat pathogens, is now implicated as a critical driver of sterile inflammation in the brain. This review synthesizes compelling evidence that in the aging and diseased central nervous system, endogenous cytosolic DNA, sourced from genomic instability, mitochondrial dysfunction, and activated retrotransposons, hijacks this pathway. Chronic cGAS-STING activation transforms microglia into inflammatory amplifiers, instigates neurotoxic astrocyte programs, and directly compromises neuronal health, creating a self-perpetuating cycle of neuroinflammation. We dissect the cell-type specific consequences within the neurovascular unit and establish the pathway's role in the pathogenesis of ALS/FTD, Alzheimer's, Parkinson's, and Huntington's diseases. Crucially, we evaluate the therapeutic potential of targeting this axis, discussing small-molecule inhibitors, oligonucleotide therapies, and upstream interventions to quell the source of immunogenic DNA. We also explicitly examine contradictory preclinical data, including the retracted PINK1-Parkin-STING report and context-dependent neurovascular findings, to provide a balanced appraisal of STING biology in the CNS. By reconciling its dual protective and pathogenic roles, this review posits cGAS-STING as a pivotal mechanism-based therapeutic node for halting the progression of neurodegenerative disorders.

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