Microglial cGAS drives neuroinflammation and neurodegeneration in mouse models of Parkinson's disease
Virus infections is associated with an increased risk of Parkinson's disease (PD). In addition, damaged or dying dopaminergic neurons can release dsDNA during PD progression. However, whether cGAS, the sensor of dsDNA, is involved in or contributes to neuroinflammation during PD remains unclear. In this study, we observed that the cGAS-STING pathway was activated during neuroinflammation in mouse models of PD. cGAS deficiency in microglia, but not peripheral myeloid cells controlled neuroinflammation and neurodegeneration during PD. Mechanistically, microglial cGAS ablation alleviated the neuronal dysfunction and inflammatory response in astrocytes and microglia by inhibiting antiviral inflammatory signaling. Additionally, the administration of cGAS inhibitors reduced the severity of PD. Collectively, these findings provide the first demonstration of cGAS in microglia driving neuroinflammation and neurodegeneration during PD progression and suggest cGAS may serve as a therapeutic target for PD patients.