Clk1 deficiency promotes neuroinflammation and subsequent dopaminergic cell death through regulation of microglial metabolic reprogramming

• Clk1/COQ7 is a mitochondrial hydroxylase that is necessary for the biosynthesis of ubiquinone.
• Reduced expression of Clk1 in microglia enhanced inflammatory responses and aerobic glycolysis.
• Inhibition of glycolysis abolished Clk1 deficiency-induced hypersensitivity to inflammation.
• mTOR/HIF-1α and ROS/HIF-1α pathways are involved in Clk1 deficiency-induced aerobic glycolysis.
• Clk1+/− mice showed more severe DA neuron loss in MPTP induced mouse model of Parkinson’s disease.

Clock (Clk)1/COQ7 is a mitochondrial hydroxylase that is necessary for the biosynthesis of ubiquinone (coenzyme Q or UQ). Here, we investigate the role of Clk1 in neuroinflammation and consequentially dopaminergic (DA) neuron survival. Reduced expression of Clk1 in microglia enhanced the LPS-induced proinflammatory response and promoted aerobic glycolysis. Inhibition of glycolysis abolished Clk1 deficiency-induced hypersensitivity to the inflammatory stimulation. Mechanistic studies demonstrated that mTOR/HIF-1α and ROS/HIF-1α signaling pathways were involved in Clk1 deficiency-induced aerobic glycolysis. The increase in neuronal cell death was observed following treatment with conditioned media from Clk1 deficient microglia. Increased DA neuron loss and microgliosis were observed in Clk1+/− mice after treatment with MPTP, a rodent model of Parkinson’s disease (PD). This increase in DA neuron loss was due to an exacerbated microglial inflammatory response, rather than direct susceptibility of Clk1+/− DA cells to MPP+, the active species of MPTP. Exaggerated expressions of proinflammatory genes and loss of DA neurons were also observed in Clk1+/− mice after stereotaxic injection of LPS. Our results suggest that Clk1 regulates microglial metabolic reprogramming that is, in turn, involved in the neuroinflammatory processes and PD.