Effects of RNA Splicing Inhibitors on Amyloid Precursor Protein Expression,ACS Omega

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Effects of RNA Splicing Inhibitors on Amyloid Precursor Protein Expression
ACS Omega ( IF 3.7 ) Pub Date : 2018-03-08 00:00:00 , DOI: 10.1021/acsomega.7b02073
Bing Bai ₁ , Sen Wang ₁ , Yuxin Chen ₁ , Jia Jia ₁ , Xinyu Tian ₁ , Chang Liu ₁ , Yanyan Xia ₁ , Hui Xie ₁

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U1 small ribonucleoproteins demonstrate proteopathy in Alzheimer’s disease, and their inhibition modulates the expression of the amyloid precursor protein (APP). We sought to determine whether this effect on the APP expression is a universal result of different kinds of RNA splicing inhibitions. We treated cells with two chemical RNA splicing inhibitors: isoginkgetin (IGK) and spliceostatin A (SSA), in which SSA reduced the APP expression, whereas IGK substantially increased it. The following western blot and reverse transcription polymerase chain reaction analyses showed that the APP expression under the IGK treatment has distinct protein forms, but the total mRNA level was nearly unchanged despite a slight switch within its three major transcripts. Further analysis revealed that the APP-increasing effect of IGK depended on protein translation and might involve inhibition in the degradation system. By immunocytochemistry, the APP likely redistributed from Golgi to endoplasmic reticulum (ER) in cells treated with IGK. When compared to the well-characterized ER-to-Golgi transport inhibitor brefeldin A, IGK showed similar APP expression patterns on the western blot. In summary, we not only determined the diverse effects of RNA splicing inhibition on the APP expression but also found the additional function of IGK on protein subcellular traffic.

中文翻译：

RNA剪接抑制剂对淀粉样前体蛋白表达的影响。

U1小核糖核蛋白在阿尔茨海默氏病中表现出蛋白病，其抑制作用调节淀粉样前体蛋白（APP）的表达。我们试图确定这种对APP表达的影响是否是不同种类的RNA剪接抑制作用的普遍结果。我们用两种化学RNA剪接抑制剂处理细胞：异银蛋白（IGK）和剪接抑素A（SSA），其中SSA降低APP的表达，而IGK大幅提高APP的表达。随后的蛋白质印迹和逆转录聚合酶链反应分析表明，在IGK处理下APP的表达具有明显的蛋白质形式，但是总mRNA水平几乎没有变化，尽管在其三个主要转录物中有轻微的切换。进一步的分析表明，IGK的APP增强作用取决于蛋白质翻译，并且可能涉及降解系统的抑制作用。通过免疫细胞化学，APP可能在用IGK处理的细胞中从高尔基体重新分布到内质网（ER）。当与特征明确的ER到高尔基体转运抑制剂布雷菲德菌素A进行比较时，IGK在Western印迹上显示出相似的APP表达模式。总之，我们不仅确定了RNA剪接抑制对APP表达的多种作用，而且还发现了IGK对蛋白质亚细胞运输的附加功能。当与特征明确的ER到高尔基体转运抑制剂布雷菲德菌素A进行比较时，IGK在Western印迹上显示出相似的APP表达模式。总之，我们不仅确定了RNA剪接抑制对APP表达的多种作用，而且还发现了IGK对蛋白质亚细胞运输的附加功能。当与特征明确的ER到高尔基体转运抑制剂布雷菲德菌素A进行比较时，IGK在Western印迹上显示出相似的APP表达模式。总之，我们不仅确定了RNA剪接抑制对APP表达的多种作用，而且还发现了IGK对蛋白质亚细胞运输的附加功能。

更新日期：2018-03-08

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