Background: Endophilin A1 (EPA1) is encoded by the SH3GL2 gene, and SH3GL2 was designated as a Parkinson’s disease (PD) risk locus by genome-wide association analysis, suggesting that EPA1 may be involved in the occurrence and development of PD. Objective: To investigate the role of EPA1 in lipopolysaccharide (LPS)-induced PD model mice. Methods: The mice PD model was prepared by injecting LPS into the substantia nigra (SN), and the changes in the behavioral data of mice in each group were observed. The damage of dopaminergic 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 were detected by western blot method. EPA1 knockdown was performed by an adeno-associated virus 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. Conclusion: 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 knockdown inhibited the NLRP1 inflammasome activation, decreased the release of inflammatory factors and ROS generation, and alleviated dopaminergic neuron damage. This indicated that EPA1 may participating in the occurrence and development of PD.
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.
Biochanin A is a natural plant estrogen, with various biological activities such as anti-apoptosis, anti-oxidation and suppression of inflammatory. In this study, we investigated the protective effects of biochanin A on AngⅡ-induced dopaminergic neurons damage in vivo and molecular mechanisms. Spontaneous activity and motor ability of mice among groups was detected by open-field test and swim-test. The expression of TH, LC3BⅡ/LC3BⅠ, Beclin-1, P62, p-FoxO3a / FoxO3a, FoxO3 and Endophilin A2 were determined by western blot and immunohistochemistry or immunofluorescence staining. Our results showed that AngⅡ treatment significantly increased the behavioral dysfunction of mice and DA neurons damage. Meanwhile, AngⅡ treatment increased the expression of LC3BⅡ/LC3BⅠ, Beclin-1, P62 and FoxO3a and decreased the expression of Endophilin A2 and p-FoxO3a / FoxO3a, however, biochanin A treatment alleviate these changes. In summary, these results suggest that biochanin A exerts protective effects on AngⅡ-induced mouse model may be related to regulating Endophilin A2, FoxO3a and autophagy-related proteins. However, the specific mechanism is not yet clear and needs further study.
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