ALDH1A1基因Alu元件插入/缺失多态性对帕金森病易感性的影响及机制研究

Parkinson’s disease (PD) is a common neurodegenerative disorder. It has been shown that aldehyde dehydrogenase 1 (gene name: ALDH1A1) plays an important protective role against PD. It can catalyze the degradation of toxic dopamine metabolite DOPAL. Therefore, we previously evaluated the association between ALDH1A1 polymorphism and PD in a Han cohort. For the first time, we identified a novel Alu element reverse insertion/deletion (Alu-I/Alu-D) polymorphism in intron 4 of ALDH1A1, and Alu-I as the risk allele for PD. Preliminary investigation suggested that Alu-I suppressed ALDH1A1 expression. Based on our experimental and reported results, we propose that Alu element can inhibit ALDH1A1 expression by altering the methylation status, the binding of transcription factors, or the alternative splicing of mRNA, which thereby enhances the susceptibility of PD. The current study aims to investigate the underlying mechanisms of the suppression of ALDH1A1 expression caused by Alu-I and the effect of Alu-I on PD susceptibility by using cellular and animal models, as well as human peripheral blood samples. Our results will have implications in understanding the complex mechanisms underlying PD pathogenesis, as well as in prevention and therapy.

帕金森病（PD）是一种常见的神经退行性疾病。已有研究显示乙醛脱氢酶1（编码基因：ALDH1A1）对PD具有重要的保护作用。该酶能够催化多巴胺有毒代谢产物（DOPAL）降解。因此，课题组前期分析了汉族人群中ALDH1A1基因多态性与PD的相关性，首次发现ALDH1A1第4内含子存在Alu元件反向插入与缺失（Alu-I/Alu-D）多态性，并且Alu-I是PD的风险等位基因。初步研究表明Alu-I可以抑制ALDH1A1的表达。结合前期工作和文献报道，我们推测Alu元件可能通过影响甲基化水平、转录因子结合或者mRNA剪接而引起ALDH1A1的表达下降，导致其保护作用降低，进而增加了PD的易感性。本项目拟从细胞、动物以及人群外周血细胞水平上，探讨Alu元件对ALDH1A1表达调控的机制和对机体PD易感性的影响。研究成果对认识PD的复杂发病机制及其预防和治疗具有一定的意义。

在动物模型中研究表明，乙醛脱氢酶1（由ALDH1A1基因编码）可通过减少多巴胺有毒代谢产物来预防帕金森氏病（PD）。本项目旨在研究人类ALDH1A1基因是否与PD易感性遗传相关及相关的机制。项目前期共招募了1039名汉族人群来分析6个标签-单核苷酸多态性（tag-SNPs）。结果发现tag-SNP rs7043217与PD易感性显著相关；同时在ALDH1A1的第4内含子中鉴定了一种新的反义Alu元件的插入/缺失多态性（命名为Yb8c4），其与rs7043217呈完全连锁不平衡。对Yb8c4的功能研究表明，Yb8c4插入可以抑制ALDH1A1基因的转录。进一步对Yb8c4调控基因表达机制的研究，排除了其通过改变基因甲基化水平和选择性剪接的可能性，而可能与引入某些转录因子位点有关。本项目的结果为ALDH1在PD发病机理中的作用提供了新的遗传机制。

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