Glut9-mediated Urate Uptake Is Responsible for Its Protective Effects on Dopaminergic Neurons in Parkinson's Disease Models.
Glut9-mediated Urate Uptake Is Responsible for Its Protective Effects on Dopaminergic Neurons in Parkinson's Disease Models.
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Glut9 介导的尿酸盐摄取对帕金森病模型中的多巴胺能神经元具有保护作用
DOI：
10.3389/fnmol.2018.00021
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发表时间：
2018
影响因子：
4.8
通讯作者：
Jiang H
中科院分区：
文献类型：
--
作者：
Bi M;Jiao Q;Du X;Jiang H
大量证据表明，血浆或脑脊液（CSF）尿酸水平升高与帕金森病（PD）风险降低相关。基于其抗氧化特性，尿酸盐可能成为PD治疗中有前途的神经保护候选物之一。然而，尿酸盐如何通过细胞膜转运并在PD细胞内发挥其作用在很大程度上是未知的。为了阐明这一点，我们发现细胞内尿酸升高对1-甲基-4-苯基吡啶（MPP+）诱导的MES23.5细胞神经毒性发挥了神经保护作用，尿酸升高可以拮抗1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的尿酸氧化酶（UOx）敲除（KO）小鼠的黑质多巴胺能神经元死亡。其转运蛋白葡萄糖转运蛋白9型（Glut9）被观察到上调，这是由p53的激活引起的。这些保护作用可被Glut9阻滞剂和p53抑制剂所消除。这些结果表明，Glut9是一种功能性的尿酸转运蛋白，其通过激活p53而上调，导致PD模型中细胞内尿酸水平升高。我们的研究结果表明，Glut9可以通过修饰来调节多巴胺能神经元中的尿酸盐水平，而不增加全身水平以避免副作用的尿酸盐升高策略可能是PD的潜在治疗靶点。
Considerable evidence has shown that elevated plasma or cerebrospinal fluid (CSF) urate levels correlated with a reduced risk of Parkinson’s disease (PD). Based on its anti-oxidative properties, urate might serve as one of promising neuroprotective candidates for PD. However, how urate is transported through cell membranes to exert its effects inside the cells in PD is largely unknown. To elucidate this, we showed that increased intracellular urate exerted its neuroprotective effects against 1-methyl-4-phenylpyridinium (MPP+)-induced neurotoxicity in MES23.5 cells and elevated urate could antagonize 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced nigral dopaminergic neuronal death in urate oxidase (UOx) knockout (KO) mice. Its transporter, glucose transporter type 9 (Glut9), was observed up-regulated, which was caused by the activation of p53. These protective effects could be abolished by Glut9 blocker and p53 inhibitor. These results suggested that Glut9 was a functional urate transporter, whose up-regulation by activation of p53 resulted in the increased intracellular urate levels in PD models. Our findings suggest that Glut9 could be modified to modulate urate levels in dopaminergic neurons and urate-elevating strategies without increasing systemic levels to avoid side effects might serve as a potential therapeutic target for PD.
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DOI：
10.1073/pnas.78.11.6858
发表时间：
1981-01-01
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES
影响因子：
--
作者：
AMES, BN;CATHCART, R;HOCHSTEIN, P
通讯作者：
HOCHSTEIN, P
影响因子：
4.7
作者：
Gong, Li;Zhang, Qi-Lin;Luo, Wei-Feng
通讯作者：
Luo, Wei-Feng
尿酸盐的神经保护作用是通过增强星形胶质细胞谷胱甘肽的合成和释放来介导的
影响因子：
6.1
作者：
Bakshi R;Zhang H;Logan R;Joshi I;Xu Y;Chen X;Schwarzschild MA
通讯作者：
Schwarzschild MA
DOI：
10.3233/jad-2010-1330
发表时间：
2010
期刊：
Journal of Alzheimer's disease : JAD
影响因子：
--
作者：
Bowman GL;Shannon J;Frei B;Kaye JA;Quinn JF
通讯作者：
Quinn JF
影响因子：
3.1
作者：
Facheris, Maurizio F.;Hicks, Andrew A.;Pramstaller, Peter P.
通讯作者：
Pramstaller, Peter P.