Neuroprotection by lactate in Parkinson's disease: A novel anti-inflammatory mechanism via 14-3-3 protein lactylation.
Neuroprotection by lactate in Parkinson's disease: A novel anti-inflammatory mechanism via 14-3-3 protein lactylation.
Where did the research take place?
The study site has not been established. Author addresses may differ from where the research occurred.
Hengyang, CN · Author affiliation
Institute of Neuroscience & Department of Physiology, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, PR China.Location evidence
Dongfeng, CN · Author affiliation
The Affiliated Nanhua Hospital, Department of Neurology, Hengyang Medical School, University of South China, 336 S Dongfeng Road, Hengyang, 421002, Hunan, PR China.Location evidence
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Original abstract
BACKGROUND: Novel therapeutic strategies for Parkinson's disease (PD) are urgently needed. Neuroinflammation is a critical driver of disease progression and represents a promising target for intervention. Emerging evidence highlights lactate as a signaling metabolite that regulates inflammatory responses through protein lactylation. Given the involvement of 14-3-3 proteins in PD pathogenesis, we investigated whether lactate confers neuroprotection by promoting 14-3-3 lactylation and modulating neuroinflammatory signaling in PD. METHODS: A rat model of PD was induced by subcutaneous injection of Rotenone (ROT) into the dorsal cervical region. Lactate was administered intracerebroventricularly. Motor function was assessed using open field, grid, and suspension tests. TH-positive neurons in the substantia nigra were evaluated by immunohistochemistry. The lactylation of 14-3-3 proteins and their interaction with NLRP3 were examined by co-immunoprecipitation (Co-IP). Mitochondrial localization of GSDMD was visualized by immunoelectron microscopy. The cytosolic mtDNA was assessed using qPCR. NLRP3 inflammasome components, the cGAS-STING pathway, and mitochondrial GSDMD were analyzed by western blotting. Levels of inflammatory cytokines and cGAMP were quantified by ELISA. RESULTS: Lactate ameliorated motor deficits and dopaminergic neuron loss in ROT-treated rats. Lactate increased 14-3-3 lactylation and enhanced 14-3-3 binding to NLRP3, accompanied by reduced NLRP3 inflammasome activation, attenuated GSDMD-associated mitochondrial injury, decreased cytosolic mtDNA levels, and suppressed cGAS-STING pathway activation. CONCLUSION: Lactate exerts neuroprotective effects in PD through a mechanism associated with enhanced 14-3-3 lactylation, reduced NLRP3/GSDMD pathway activation, attenuated GSDMD-associated mitochondrial injury, decreased cytosolic mtDNA levels, and suppression of cGAS-STING signaling.