Protocatechuic acid alleviates cGAS-STING-mediated neuroinflammation by enhancing microglial autophagy in mouse models of Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is a prevalent neurodegenerative disorder characterized by dopaminergic neuron loss and neuroinflammation. The cGAS-STING pathway-mediated innate immune inflammation has been implicated in PD pathogenesis, but its interplay with autophagy in PD remains poorly understood. Protocatechuic acid (PCA), a bioactive polyphenol metabolite, exhibits neuroprotective properties; however, its effects on autophagy and cGAS-STING signaling in PD has not been investigated.

PURPOSE: This study aimed to elucidate the neuroprotective effects of PCA against PD and its underlying mechanisms in suppressing cGAS-STING-mediated inflammation.

METHODS: Using N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced and A30P transgenic PD mouse models, we evaluated the neuroprotective effects of PCA through behavioral tests and immunohistochemistry. And we examined the changes in cGAS-STING pathway and related inflammation using qPCR, ELISA, and western blotting. Primary microglia cultures and microglia-specific Atg5 knockout mice were employed to dissect the role of autophagy in PCA-mediated inhibition of cGAS-STING signaling.

RESULTS: PCA administration alleviated motor deficits, reduced dopaminergic neuron loss, and suppressed neuroinflammation in the PD models. Mechanistically, PCA enhanced autophagy, promoting the clearance of damaged DNA and inhibiting cGAS-STING pathway activation, as evidenced by the reduced phosphorylation of TBK1, IRF3, and NF-κB. Microglial Atg5 deletion abolished the anti-inflammatory and neuroprotective effects of PCA, confirming its autophagy dependence. In A30P mice, PCA also attenuated α-synuclein aggregation and improved motor function.

CONCLUSION: Our study identifies a novel mechanism linking natural metabolite PCA to the autophagy-cGAS-STING axis in PD. Our findings highlight the critical crosstalk between autophagy and innate immunity in PD pathogenesis and propose PCA as a promising disease-modifying strategy.