The Double-Edged Sentinel: cGAS-STING as a Context-Dependent Regulator of Microglial Senescence and Neuronal Genotoxic Stress in Neurodegeneration.

BACKGROUND: Neurodegenerative diseases may continue to progress even when a pathogenic protein aggregate is reduced, suggesting that downstream inflammatory and genotoxic circuits can become partly autonomous. This narrative review examines cGAS-STING as a context-dependent regulator of DNA-stress responses in the ageing and proteinopathic brain. METHODS: PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar were searched for mechanistic, translational, and human-tissue studies of cGAS-STING, DNA damage, mitochondrial quality control, neuroinflammation, and major neurodegenerative diseases. Evidence was separated into biochemical or cellular, animal, and human observations, and contradictory findings were retained. RESULTS: Mitochondrial DNA leakage is a recurrent candidate trigger, while activity-induced nuclear DNA breaks, defective repair, retrotransposon-derived cDNA, and micronuclear rupture provide conditional inputs. Microglial evidence is currently more extensive and causally developed than neuron-specific evidence; neuronal STING is most firmly supported in selected contexts such as excitotoxic or ischemic stress. Across Alzheimer disease, Parkinson disease, ALS/FTD, multiple sclerosis, and Huntington disease, cGAS-STING-associated inflammation is plausible but not uniform, and human validation remains limited. Therapeutic strategies therefore require cell-, source-, and stage-aware modulation rather than indiscriminate pathway ablation. CONCLUSION: cGAS-STING is best regarded as a testable kinetic-bottleneck model, not a universal driver of neurodegeneration. Longitudinal human studies and cell-resolved biomarkers are needed to determine when recalibration can suppress pathological inflammation while preserving antiviral and homeostatic functions.