Pael receptor is involved in dopamine metabolism in the nigrostriatal system
Pael receptor is involved in dopamine metabolism in the nigrostriatal system
复制标题
DOI：
10.1016/j.neures.2007.08.005
复制
发表时间：
2007-12-01
影响因子：
2.9
通讯作者：
Takahashi, Ryosuke
中科院分区：
文献类型：
--
作者：
Imai, Yuzuru;Inoue, Haruhisa;Takahashi, Ryosuke
Pael受体（Pael-R）是Parkin的底物之一，Parkin是一种泛素连接酶，可引起常染色体隐性遗传性幼年型帕金森综合征（AR-JP）。当Parkin失活时，未折叠的Pael-R在内质网中积聚，并通过未折叠的蛋白应激导致神经元死亡，这表明Pael-R在AR-JP的发病机制中发挥重要作用。在这里，我们报告了Pael-R缺陷（KO）和Pael-R转基因（Tg）小鼠的分析。Pael-R KO小鼠纹状体多巴胺（DA）含量仅为正常小鼠的60%，而Pael-R Tg小鼠纹状体3，4-二羟基苯乙酸（DOPAC）和囊泡DA含量均升高。此外，Pael-R Tg小鼠黑质纹状体多巴胺能神经元更易受到帕金森病相关神经毒素的伤害，而Pael-R KO小鼠则较少，这些结果强烈地表明Pael-R信号调节多巴胺能神经元中DA的含量，并且Pael-R过度表达使多巴胺能神经元更易受到慢性DA毒性的影响。(C)2007 Elsevier爱尔兰有限公司和日本神经科学学会。All rights reserved.
Pael receptor (Pael-R) has been identified as one of the substrates of Parkin, a ubiquitin ligase responsible for autosomal recessive juvenile Parkinsonism (AR-JP). When Parkin is inactivated, unfolded Pael-R accumulates in the endoplasmic reticulum and results ill neuronal death by unfolded protein stress, suggesting that Pael-R has an important role in the pathogenesis of AR-JP. Here we report the analyses on Pael-R-deficient (KO) and Pael-R-transgenic (Tg) mice. The striatal dopamine (DA) level of Pael-R KO mice was only 60% of that in normal mice, while in Pael-R Tg mice, striatal 3,4-dihydroxyphenylacetic acid (DOPAC) as well as vesicular DA content increased. Moreover, the nigrostriatal dopaminergic neurons of Pael-R Tg mice are more vulnerable to Parkinson's disease-related neurotoxins while those of Pael-R KO mice are less. These results strongly suggest that the Pael-R signal regulates the amount of DA in the dopaminergic neurons and that excessive Pael-R expression renders dopaminergic neurons susceptible to chronic DA toxicity. (C) 2007 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.