The role and Mechanism of Endophilin A1 in LPS-induced Parkinson's disease model mice

Abstract

Background: Neuroinflammation and oxidative stress are closely related to the pathogenesis of Parkinson's disease (PD), and PD is pathologically characterized by progressive loss of dopaminergic neurons in the SN pars compacta and excessive accumulation of α-synuclein. Endophilin A1(EPA1) is a cytoplasmic protein that is widely expressed in presynaptic nerve terminals in the brain and regulates synaptic vesicle cycling. EPA1 is encoded by the SH3GL2 gene, and SH3GL2 was designated as a PD risk locus by genome-wide association analysis, suggesting that EPA1 may be involved in the occurrence and development of PD. However, the role of EPA1 in PD remains unclear.Methods: The mice PD model was prepared by injecting LPS into the SN, and the changes in the behavioral data of mice in each group were observed through grasping force and open-field behavioral experiments. The damage of DA neurons, activation of microglia, and reactive oxygen species (ROS) generation were detected by immunofluorescence method; calcium ion concentration was detected by calcium content detection kit; EPA1 and inflammation and its related indicators (NLRP1, ASC, Caspase-1, IL-1β, IL-18, IL-6, TNF-α) were detected by Western blot method. EPA1 knockdown was performed by an adeno-associated virus (AAV) vector containing EPA1-shRNA-eGFP infusion.Results: LPS-induced PD model mice developed behavioral dysfunction, SN dopaminergic nerve damage, significantly increased calcium ion, calpain 1, and ROS production, activated NLRP1 inflammasome and promoted pro-inflammatory cell release, and SN EPA1 knockdown improves behavioral disorders, alleviates dopaminergic neuron damage, reduces calcium, calpain 1, ROS generation, and blocks NLRP1 inflammasome-driven inflammatory responses.Conclusions: The expression of EPA1 in the SN of LPS-induced PD model mice was increased, and it played a role in promoting the occurrence and development of PD. EPA1 activates the NLRP1 inflammasome to promote the release of inflammatory factors by regulating calcium ion homeostasis and ROS generation, and induces DA neuron damage through an inflammatory mechanism, thereby participating in the occurrence and development of PD.