Crosstalk between DNA damage and cGAS-STING immune pathway drives neuroinflammation and dopaminergic neurodegeneration in Parkinson's disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder marked by substantial degeneration of dopaminergic neurons in the substantia nigra and dopamine depletion in the striatum, leading to debilitating motor and non-motor impairments. Recent studies provide clues on the pathogenic role of DNA damage in age-related neurodegenerative diseases, but the molecular mechanisms of DNA damage response in PD remain poorly understood. We found that the accumulation of DNA double-strand breaks (DDSBs), and/or DNA repair deficits, are key in the pathogenesis of PD and drives cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) immune regulatory pathway, contributing to neuroinflammation and dopaminergic neurodegeneration in human postmortem PD and non-PD brains as well as in experimental models of PD. We observed enhanced expression of γ-H2A.X (Ser139) a biomarker of DDSB, and decreased levels of DNA repair proteins in the brains of human PD compared to non-PD brains. This was positively correlated with upregulation of STING immune response pathways, microglial activation, senescence and dopaminergic neurodegeneration. Similarly, we observed increased and sustained DDSB as assessed by γ-H2A.X (Ser139) immunoreactivity, and degeneration of tyrosine hydroxylase-positive neurons in primary neuron/glia cultures and mice treated with 1-methyl-4-phenylpyridine (MPP+) or 1,2,3,6-tetrahydropyridine (MPTP). Next, we employed a mouse model of α-synucleinopathy, which exhibited elevated DDSBs alongside overactivation of the DNA-sensing cGAS-STING pathway and type-I interferon signaling, in association with dopaminergic neurodegeneration. Interestingly, pharmacological and genetic ablation of STING reduces DDSB, limits inflammatory response, improves behavioral function and attenuates the loss of dopaminergic neurons in this model. Our findings suggest that the accumulation of DDSBs and/or dysregulation in DNA repair proteins activate cGAS-STING mediated immune responses in the brain, potentially exacerbating dopaminergic neurodegeneration in PD. Furthermore, regulating these processes is essential for alleviating the pathological effects of PD and may offer potential therapeutic strategies.