Glut9-mediated increased intracellular urate levels are responsible for its protective effects on dopaminergic neurons in Parkinson's disease
作者单位：Department of Physiology Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders State Key Disciplines: Physiology Medical College of Qingdao University
会议名称：《中国神经科学学会第十二届全国学术会议》
会议日期：2017年
学科分类：1002[医学-临床医学] 100204[医学-神经病学] 10[医学]
关 键 词：Parkinson’s disease urate Glut9 p53 oxidative stress
摘 要：Objective Considerable evidence had shown that elevated plasma or cerebrospinal fluid(CSF) urate correlated with a reduced risk and slow progression of Parkinson’s disease(PD). Based on its anti-oxidative properties, urate might serve as one of promising neuroprotective candidates for PD. The present study is aimed to explore the mechanism underlying the transport of urate through the cell membrane. Methods To elucidate this, using urate oxidase(UOx) knockout mice and MES23.5 dopaminergic cells, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-induced mice model and 1-methyl-4-phenylpyridillium ion(MPP)-induced cell model of PD were employed for in vivo and in vitro studies, respectively. The effects of urate on dopaminergic neurons were investigated by measuring tyrosine hydroxylase(TH) positive neurons and oxidative stress index. Intracellular urate levels were detected by urate fluorometric assay. The underlying urate transport mechanism was also explored. Results In the present study, we found that urate could antagonize MPP-induced decrease in cell viability and oxidative injury, resulting in the decreased reactive oxygen species(ROS) generation, increased mitochondrial membrane potential(ΔΨm) and superoxide dismutase(SOD) levels in MES23.5 dopaminergic cells. Increased intracellular urate levels were responsible for this neuroprotective effect, which was caused by the up-regulation of its transporter, glucose transporter type 9(Glut9). Moreover, we found that the activation of p53 led to the increased Glut9 levels. These protective effects could be completely abolished by specific inhibition of Glut9 and p53. While in UOx knockout mice with elevated serum and striatal urate levels, MPTP even could not cause damage to the nigral dopaminergic neurons. Conclusion The up-regulation of Glut9 was capable of increasing intracellular urate levels under oxidative stresss conditions, which might serve as an endogenous compensatory mechanism for adaptation to oxidative