MPTP诱导的帕金森病小鼠模型黑质脑组织DNA甲基化研究

被引：8

作者：

胡雅岑 ^{[1
]}

徐倩 ^{[2
]}

郭纪峰 ^{[2
,3
]}

艾三喜 ^{[2
]}

宋承远 ^{[2
]}

孙启英 ^{[1
]}

翁翎 ^{[2
]}

周琳 ^{[1
]}

江泓 ^{[2
,3
]}

沈璐 ^{[2
,3
]}

严新翔 ^{[2
,3
]}

唐北沙 ^{[2
,3
,4
]}

机构：

[1] 中南大学湘雅医院老年病学神经内科

[2] 中南大学湘雅医院神经内科

[3] 神经退行性疾病湖南省重点实验室

[4] 中南大学医学遗传学国家重点实验室

来源：

生物化学与生物物理进展 | 2015年 / 42卷 / 03期

关键词：

帕金森病; DNA甲基化; 总体甲基化; DNA甲基转移酶; 泛素羧基末端水解酶1;

D O I：

10.16476/j.pibb.2014.0120

中图分类号：

R742.5 [震颤麻痹综合征]; R-332 [医用实验动物学];

学科分类号：

1002 ; 1001 ;

摘要：

为研究DNA甲基化在帕金森病发病机制中的作用,本研究用环境毒素1-甲基-4-苯基-1,2,3,6-四氢吡啶(MPTP)连续腹腔给药诱导小鼠帕金森病(Parkison’s disease,PD)模型,应用ELISA检测小鼠黑质脑组织总体甲基化水平,应用实时荧光定量PCR方法检测DNA甲基转移酶表达水平,探讨MPTP诱导的小鼠PD模型黑质部位是否存在DNA甲基化异常.进一步应用甲基化DNA免疫共沉淀结合DNA甲基化芯片方法,构建MPTP诱导的小鼠PD模型黑质脑组织DNA甲基化谱,并寻找DNA甲基化修饰异常的PD相关基因对其进行验证.结果表明,模型组小鼠黑质脑组织DNA总体甲基化水平较对照组显著降低,Dnmt1的表达水平显著增高.利用DNA甲基化芯片在全基因组内筛选出甲基化差异修饰位点共48个,涉及44个基因,这些甲基化差异基因参与信号转导、分子转运、转录调控、发育、细胞分化、凋亡调控、氧化应激、蛋白质降解等生物学过程.在甲基化差异修饰基因中,对Uchl1基因及Arih2基因进行了甲基化水平以及表达水平的验证.结果表明,模型组小鼠黑质脑组织Uchl1启动子区域甲基化水平较对照组增高,m RNA及蛋白质表达水平降低,Arih2启动子区域甲基化水平较对照组降低,m RNA及蛋白质表达水平增高.实验结果进一步证实,DNA甲基化修饰异常在帕金森病发病机制中有重要作用,环境因素(如MPTP)可以通过改变DNA甲基化修饰参与帕金森病的发生发展.

引用

页码：277 / 285

页数：9

共 16 条

[1]

Promoter methylation analysis of seven clock genes in Parkinson’s disease[J] . Qingling Lin,Hui Ding,Zheng Zheng,Zhuqin Gu,Jinghong Ma,Ling Chen,Piu Chan,Yanning Cai.Neuroscience Letters . 2011 (2)

[2] The Parkin-Like Human Homolog of Drosophila Ariadne-1 (HHARI) Can Induce Aggresome Formation in Mammalian Cells and Is Immunologically Detectable in Lewy Bodies [J].

Parelkar, Sangram S. ;

Cadena, Juan G. ;

Kim, Chul ;

Wang, Zhaohui ;

Sugal, Rachel ;

Bentley, Brooke ;

Moral, Luis ;

Ardley, Helen C. ;

Schwartz, Lawrence M. .

JOURNAL OF MOLECULAR NEUROSCIENCE, 2012, 46 (01) :109-121

[3]

Gene expression profiling in progressively MPTP-lesioned macaques reveals molecular pathways associated with sporadic Parkinson’s disease[J] . Tatsuya Ohnuki,Atsushi Nakamura,Shigeru Okuyama,Shoji Nakamura.Brain Research . 2010

[4] DNA Methylation of Alzheimer Disease and Tauopathy-Related Genes in Postmortem Brain [J].

Barrachina, Marta ;

Ferrer, Isidre .

JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY, 2009, 68 (08) :880-891

[5]

Different methylation of the TNF-alpha promoter in cortex and substantia nigra: Implications for selective neuronal vulnerability[J] . Heike C. Pieper,Bernd O. Evert,Oliver Kaut,Peter F. Riederer,Andreas Waha,Ullrich Wüllner.Neurobiology of Disease . 2008 (3)

[6]

Excessive S -adenosyl- l -methionine-dependent methylation increases levels of methanol, formaldehyde and formic acid in rat brain striatal homogenates: Possible role in S -adenosyl- l -methionine-induced Parkinson’s disease-like disorders[J] . Eun-Sook Lee,Hongtao Chen,Chadwick Hardman,Anthony Simm,Clivel Charlton.Life Sciences . 2008 (25)

[7] Homocysteine is toxic for dopaminergic neurons in primary mesencephalic culture [J].

Imamura, Keiko ;

Takeshima, Takao ;

Nakaso, Kazuhiro ;

Nakashima, Kenji .

NEUROREPORT, 2007, 18 (13) :1319-1322

[8] Transcriptome analysis reveals link between proteasomal and mitochondrial pathways in Parkinson's disease [J].

Duke, D. C. ;

Moran, L. B. ;

Kalaitzakis, M. E. ;

Deprez, M. ;

Dexter, D. T. ;

Pearce, R. K. B. ;

Graeber, M. B. .

NEUROGENETICS, 2006, 7 (03) :139-148

[9]

Acute intranigral homocysteine administration produces stereotypic behavioral changes and striatal dopamine depletion in Sprague–Dawley rats[J] . Goutam Chandra,Prasanta K. Gangopadhyay,Karuppagounder S. Senthil Kumar,Kochupurackal P. Mohanakumar.Brain Research . 2005 (1)

[10] Effects of homocysteine on the dopaminergic system and behavior in rodents [J].

Lee, ESY ;

Chen, HT ;

Soliman, KFA ;

Charlton, CG .

NEUROTOXICOLOGY, 2005, 26 (03) :361-371

← 1 2 →