Clk1 Deficiency Promotes Neuroinflammation And Subsequent Neuronal Cell Death Through Regulation Of Microglial Metabolic Reprogramming

Clk1/COQ7 is a mitochondrial hydroxylase that is necessary for the biosynthesis of ubiquinone?coenzyme Q or UQ?,the essential electron transporter of the mitochondrial respiratory chain.Here,we investigate the role of Clk1 in the regulation of neuroinflammation.Reduced expression of Clk1 in microglia cells enhanced the LPS-induced proinflammatory response and promoted aerobic glycolysis.Inhibition of glycolysis abolished Clk1 deficiency-induced hypersensitivity to the inflammatory response.Mechanistic studies demonstrated that mTOR/HIF-1?and ROS/HIF-1?signaling pathways are involved in Clk1 deficiency-induced aerobic glycolysis.Increase in neuronal cell death was observed following treatment with conditioned media from Clk1 deficient microglia.Moreover,increased DA neuron loss and microgliosis were observed in Clk1^+/-mutant mice after treatment with MPTP,a rodent model of Parkinson's disease?PD?.This increase in dopaminergic neuron loss was likely due to an exacerbated microglial inflammatory response,rather than direct susceptibility of Clk1^+/-mutant neuronal cells to MPP⁺,the active species of MPTP.Consistent with this,exaggerated expression of proinflammatory genes and loss of dopaminergic neurons were also observed in Clk1^+/-mutant mice in the stereotaxic LPS injection model.Our results suggest that Clk1 regulates microglial metabolic reprogramming that is,in turn,involved in the neuroinflammatory processes and pathological development of PD.