title: Clk1 deficiency promotes neuroinflammation and subsequent dopaminergic cell death through regulation of microglial metabolic reprogramming.
abstract: 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.
authors: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215021, China.
authors: Ruinan
authors: R
authors: Gu
authors: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215021, China.
authors: Fali
authors: F
authors: Zhang
authors: Nanjing Galaxy Biopharma Co. Ltd., 12 Xuefu Road, Pukou High Tech District, Nanjing, Jiangsu 210016, China.
authors: Gang
authors: G
authors: Chen
authors: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215021, China.
authors: Chaojun
authors: C
authors: Han
authors: Nanjing Galaxy Biopharma Co. Ltd., 12 Xuefu Road, Pukou High Tech District, Nanjing, Jiangsu 210016, China.
authors: Jay
authors: J
authors: Liu
authors: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215021, China.
authors: Zhaoxiang
authors: Z
authors: Ren
authors: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215021, China.
authors: Yi
authors: Y
authors: Zhu
authors: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215021, China; Molecular & Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
authors: John L
authors: JL
authors: Waddington
authors: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215021, China. Electronic address: zhenglongtai@suda.edu.cn.
authors: Long Tai
authors: LT
authors: Zheng
authors: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215021, China. Electronic address: xuechuzhen@suda.edu.cn.
authors: Xuechu
authors: X
authors: Zhen
mesh_terms: D000818:Animals; D016923:Cell Death / Q000235:genetics*; D002478:Cells, Cultured; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism*; D009410:Nerve Degeneration / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency*; D011505:Protein-Tyrosine Kinases / Q000172:deficiency*
chemical_list: D008070:Lipopolysaccharides; C066780:Clk dual-specificity kinases; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D004298:Dopamine
keywords: Clk1; Glycolysis; MPTP; Microglia; mTOR/HIF-1α