Deletion of Calhm2 alleviates MPTP-induced Parkinson's disease pathology by inhibiting EFHD2-STAT3 signaling in microglia

Background: Neuroinflammation is involved in the development of Parkinson's disease (PD).Calhm2 plays an important role in the development of microglial inflammation, but whether Calhm2 is involved in PD and its regulatory mechanisms are unclear.Methods: To study the role of Calhm2 in the development of PD, we utilized conventional Calhm2 knockout mice, microglial Calhm2 knockout mice and neuronal Calhm2 knockout mice, and established the MPTP-induced PD mice model.Moreover, a series of methods including behavioral test, immunohistochemistry, immunofluorescence, real-time polymerase chain reaction, western blot, mass spectrometry analysis and co-immunoprecipitation were utilized to study the regulatory mechanisms.Results: We found that both conventional Calhm2 knockout and microglial Calhm2 knockout significantly reduced dopaminergic neuronal loss, and decreased microglial numbers, thereby improving locomotor performance in PD model mice.Mechanistically, we found that Calhm2 interacted with EFhd2 and regulated downstream STAT3 signaling in microglia.Knockdown of Calhm2 or EFhd2 both inhibited downstream STAT3 signaling and inflammatory cytokine levels in microglia. Conclusion:We demonstrate the important role of Calhm2 in microglial activation and the pathology of PD, thus providing a potential therapeutic target for microglia-mediated neuroinflammation-related diseases.