Epigenetic upregulation of alpha-synuclein in the rats exposed to methamphetamine
Epigenetic upregulation of alpha-synuclein in the rats exposed to methamphetamine
复制标题
DOI：
10.1016/j.ejphar.2014.10.043
复制
发表时间：
2014-12-15
影响因子：
5
通讯作者：
Wang, Zhejian
中科院分区：
文献类型：
--
作者：
Jiang, Wenda;Li, Ji;Wang, Zhejian
甲基苯丙胺（METH）的滥用增加了个体发生帕金森病（PD）的风险。突触蛋白（i-突触核蛋白（由Sum基因编码））的表达增加与PD患者的神经元丢失和运动功能障碍显著相关。本研究的目的是探讨潜在的表观遗传机制的α-突触核蛋白在黑质的表达改变，在大鼠先前暴露于甲基。暴露于甲基诱导显着的行为障碍，在转棒测试和开放领域的测试，以及黑质细胞因子合成的上调。在暴露于METH的大鼠的黑质中也观察到α-突触核蛋白的表达显著增加。进一步的染色质免疫沉淀和亚硫酸氢盐测序研究显示，在暴露于METH的大鼠中，Snca启动子区域的胞嘧啶甲基化显著降低。结果发现，模型组大鼠黑质中Slim启动子区甲基CpG结合蛋白2和DNA甲基转移酶1的占有率也明显降低。这些结果加深了我们对有METH使用史的个体中PD发病率增加的机制的理解，并为这种神经系统疾病患者的治疗方法的发展提供了新的思路。(C)2014 Elsevier BA/. All rights reserved.
Abuse of methamphetamine (METH) increases the risk of occurrence of Parkinson's disease (PD) in the individuals. Increased expression of synaptic protein (i-synuclein (encoded by gene Sum) is remarkably associated with the neuronal loss and motor dysfunction in the patients with PD. The present study aimed to explore the epigenetic mechanism underlying the altered expression of alpha-synuclein in substantia nigra in the rats previously exposed to METH. Exposure to METH induced significant behavioral impairments in the rotarod test and open field test, as well as the upregulation of cytokine synthesis in the substantia nigra. Significantly increased expression of alpha-synuclein was also observed in the substantia nigra in the rats exposed to METH. Further chromatin immunoprecipitation and bisulfite sequencing studies revealed a significantly decreased cytosine methylation in the Snca promoter region in the rats exposed to METH. It was found that the occupancy of methyl CpG binding protein 2 and DNA methyltransferase 1 in Slim promoter region was also significantly decreased in the substantia nigra in the modeled rats. These results advanced our understanding on the mechanism of the increased incidence of PD in the individuals with history use of METH, and shed novel lights on the development of therapeutic approaches for the patients conflicted with this neurological disorder. (C) 2014 Elsevier BA/. All rights reserved.