OBJECTIVE To investigate the effect of clk1 gene in MPTP mouse model to identify the function of clk1 gene in Parkinsons disease.METHODS Subchronic MPTP mouse model (MPTP, 30 mg·kg-1, 5 d) was employed in male Mclk1+/-mutant mice and wide type C57BL/J mice (WT).Behavioral tests were performed 7 d after MPTP injection, immunological histochemistry(IHC)was carried on after behavioral tests.Primary astrocyte of WT and Mclk1+/-mutant was used to investigate the role of clk1 in inflammatory response.The expression of inflammatory cytokines and proinflammatory factors were assessed by real-time PCR, ELISA and NO assay.The role of clk1 in the intracellular level of reactive oxygen species (ROS) generation and mitochondrial membrane potential were also investigated by using fluorescent probe DCFHDA and JC-1, respectively.MTT assay were used to detect the neuronal viability in glial conditioned medium/neuron co-culture system.The expression of HIF-1α, TH and GFAP in brain tissue and astrocyte were detected by western blotting.RESULTS In vivo, at the basal level,Mclk1+/-mutant appeared no obvious differences compared with WT.However, in the subchronic MPTP mouse model, Mclk1+/-mutant mice showed more neuron loss and increased glial cells compared with wild-type mice consistent with the behavioral appearance.In vitro,Mclk1+/-glial cells treated with LPS/IFN-γexpressed increased amounts of the proinflammatory cytokines, produced higher intracellular ROS and had lower mitochondrial membrane potential probably via HIF-1α, and conditioned media from these cells promoted death of cultured neurons.CONCLUSION These findings suggest that the exacerbated neuron loss was likely due to vulnerability of Mclk+/-neurons to MPTP, as well as an increased neuroglial inflammatory response.