The leaked mitochondrial DNA activated the cGAS-STING signaling pathway and exacerbated the motor dysfunction in mice caused by MPTP.

Parkinson's disease (PD) is the fastest-growing neurological disorder worldwide, outpacing even the rate of population aging. The Global Burden of Disease Study estimated that more than 10 million individuals were affected in 2020, a figure projected to double by 2040. Pathologically, PD is characterised by the progressive degeneration of dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNc). Although early mechanistic work centred on gross anatomical changes and neuronal injury, converging evidence now positions neuroinflammation as an early and causal driver of DA neurodegeneration across the entire PD continuum. While cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING)-dependent innate immune signaling has been implicated in several neurodegenerative disorders, its contribution to PD has remained undefined. Here, using complementary in vitro and in vivo PD models, we demonstrate that mitochondrial stress triggers mitochondrial DNA (mtDNA) leakage into the cytosol, thereby activating the cGAS-STING pathway and precipitating SNcDA neuronal loss and overt motor dysfunction. Genetic knockdown of STING markedly attenuated DA neuronal demise and preserved motor performance, identifying STING-mediated neuroinflammation as a critical mediator of DAergic neurodegeneration in MPTP-induced motor deficits. Collectively, our data indicate that selective inhibition of the cGAS-STING inflammatory cascade robustly mitigates MPTP-induced nigrostriatal DA neurodegeneration and motor deficits in mice, and nominate this pathway as a tractable therapeutic target for disease-modifying intervention in PD.