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.