2012年12月21日,，國際學(xué)術(shù)期刊《International Journal of Biochemistry and Cell Biology》在線發(fā)表了 生化與細(xì)胞所張學(xué)軍研究組的最新研究成果—“Acetylcholinesterase deficiency decreases apoptosis in dopaminergic neurons in the neurotoxin model of Parkinson’s disease”。該研究不僅證實(shí)了乙酰膽堿酯酶Acetylcholinesterase（AChE）確實(shí)參與到了帕金森疾?。≒arkinson’s disease）模型中黑質(zhì)區(qū)域多巴胺能神經(jīng)元的凋亡過程,，而且發(fā)現(xiàn)在相同條件的藥物誘導(dǎo)所建立的模型中,，小鼠黑質(zhì)區(qū)域AChE的表達(dá)量與多巴胺能神經(jīng)元的損傷程度在一定程度上呈正相關(guān)關(guān)系,。該研究為完善帕金森疾病發(fā)病過程中細(xì)胞凋亡調(diào)控網(wǎng)絡(luò)提供新線索，也將有可能為帕金森疾病這種神經(jīng)退行性疾病提供新靶標(biāo)和候選性肽類新藥物,。
帕金森疾病作為常見的老年性神經(jīng)退行性疾病,，在60歲以上的老年人群中的發(fā)病率正逐年上升。其初期表現(xiàn)為四肢震顫,，行為遲緩,，肌肉僵直，晚期認(rèn)知障礙和行為障礙將更為嚴(yán)重,，甚至癡呆,。帕金森最主要的病理改變是中腦黑質(zhì)區(qū)域多巴胺能神經(jīng)元的死亡，由此而引起紋狀體內(nèi)多巴胺含量顯著性減少而致病,。但是其確切病因還不清楚,，被認(rèn)為與遺傳因素、環(huán)境因素,、年齡老化,、氧化應(yīng)激相關(guān)。所以目前所使用的治療手段只能改善癥狀,，不能阻止病情的進(jìn)展,，也無法治愈疾病。
張學(xué)軍研究組長期以來致力于研究AChE在細(xì)胞凋亡過程中發(fā)揮的作用,。以往研究發(fā)現(xiàn),，幾乎來源所有組織的凋亡細(xì)胞中，均能表達(dá)AChE,。而且在腎臟缺血再灌注模型及糖尿病模型中,，AChE也被證實(shí)參與到了細(xì)胞凋亡相關(guān)的病理過程中。猜測AChE可能在帕金森疾病發(fā)病過程中也起到一定的作用,。期望通過建立帕金森疾病的細(xì)胞及動(dòng)物模型研究AChE與帕金森疾病發(fā)病機(jī)理的關(guān)系,。博士研究生張雪瑾等在張學(xué)軍研究員的指導(dǎo)下，通過一系列的體外細(xì)胞實(shí)驗(yàn)和體內(nèi)動(dòng)物實(shí)驗(yàn),，發(fā)現(xiàn)無論是在體外1-methyl-4-phenylpyridinium（MPP+）細(xì)胞模型還是在體內(nèi)1,2,3,6-tetrahydropyridine (MPTP)小鼠模型中,，都證實(shí)了AChE參與了帕金森疾病模型中，中腦黑質(zhì)區(qū)域多巴胺能神經(jīng)元的凋亡過程,。在進(jìn)一步的研究中,，利用AChE基因敲除小鼠建立帕金森疾病模型，發(fā)現(xiàn)AChE表達(dá)量較少的AChE基因敲除雜合子小鼠的的黑質(zhì)區(qū)域多巴胺能神經(jīng)元的細(xì)胞凋亡比例明顯小于野生型小鼠,，相應(yīng)的細(xì)胞凋亡標(biāo)志蛋白caspase系列蛋白剪切也明顯減少,。這一發(fā)現(xiàn)提示AChE表達(dá)的缺失對(duì)帕金森疾病模型中的多巴胺能神經(jīng)元有一定的保護(hù)作用，為研究帕金森疾病的發(fā)病機(jī)理提供了新的思路,。
該項(xiàng)工作得到了國家自然科學(xué)基金的支持,。(生物谷Bioon.com)
DOI:10.1016/j.biocel.2012.11.015
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Acetylcholinesterase deficiency decreases apoptosis in dopaminergic neurons in the neurotoxin model of Parkinson's disease
Xuejin Zhang1, Lu Lu1, Shengjun Liu, Weiyuan Ye, Jun Wu, Xuejun Zhang,
The apoptosis pathway has been proposed to be involved in causing neuronal cell death in the pathogenesis of Parkinson's disease. However, the details of this pathway are poorly understood. Previous research has shown increased acetylcholinesterase expression during apoptosis in various cell types, which suggests that acetylcholinesterase has a potential role in neuronal cell death. In this study, we found that acetylcholinesterase protein expression increased and caspase-3 was activated in PC12 cells treated with 1-methyl-4-phenylpyridinium. Furthermore, the genetic or pharmacological inhibition of acetylcholinesterase was shown to protect PC12 cells from MPP+ induced apoptotic cell death. To study the function of acetylcholinesterase as a mechanism of neuronal cell death in vivo, we subsequently established a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine Parkinson's disease mouse model utilizing acetylcholinesterase-deficient mice. Studies in these mice revealed reduced dopaminergic neuron loss and lower expression levels of apoptotic proteins in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated heterozygous mice compared to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated wild-type mice. We conclude that it is highly probable that acetylcholinesterase is involved in the pathogenesis of the neurotoxin model of Parkinson's disease via apoptosis. Specifically, a deficiency or inhibition of acetylcholinesterase can decrease apoptosis and protect dopaminergic neurons in the neurotoxin model of Parkinson's disease.
