Cheng Zhi, Du Zhanqiang, Shang Yingchun, Zhang Yuling, Zhang Tao
College of Life Sciences and Key Laboratory of Bioactive Materials Ministry of Education, Nankai University, 300071, Tianjin, People's Republic of China.
School of Medicine, Nankai University, 300071, Tianjin, People's Republic of China.
J Mol Neurosci. 2017 Aug;62(3-4):269-275. doi: 10.1007/s12031-017-0932-y. Epub 2017 Jun 3.
U1 small nuclear RNA (snRNA) is selectively enriched in 100% of familial Alzheimer's disease (AD) resulting from presenilin1 (PS1) and amyloid precursor protein (APP) mutations. However, it remains unknown what gene or protein cause the U1 snRNA overexpression and then resulted in AD. Using SH-SY5Y cells, we discovered that PS1 induced the overexpression of U1 snRNA, which increased the production of Aβ. Moreover, the U1 snRNA overexpression induced the upregulation of apoe and clu transcripts. In addition, the levels of phosphorylation of tau protein at Thr212 were significantly elevated in U1 snRNA overexpression cells. Immunofluorescence using antibodies reactive with the phosphorylation of tau at Thr212 site demonstrated the hyperphosphorylated tau localization with α-tubulin, the main component of cytoskeleton. Importantly, the increased levels of Bax, Bcl2, and Bax/Bcl2 ratio showed that the overexpression of U1 snRNA could cause cell apoptosis. Conclusively, these findings suggest that PS1 considerably increases the level of U1snRNA accompanied with the adverse change of Aβ level, AD-related tau cytoskeletal pathology, and cell apoptosis.
U1小核RNA（snRNA）在由早老素1（PS1）和淀粉样前体蛋白（APP）突变导致的100%家族性阿尔茨海默病（AD）中选择性富集。然而，尚不清楚是何种基因或蛋白质导致U1 snRNA过表达进而引发AD。利用SH-SY5Y细胞，我们发现PS1诱导U1 snRNA过表达，这增加了Aβ的产生。此外，U1 snRNA过表达诱导了载脂蛋白E（apoe）和集群蛋白（clu）转录本的上调。另外，在U1 snRNA过表达的细胞中，苏氨酸212位点的tau蛋白磷酸化水平显著升高。使用与苏氨酸212位点tau磷酸化反应的抗体进行免疫荧光检测，结果显示高磷酸化的tau与细胞骨架的主要成分α-微管蛋白共定位。重要的是，Bax、Bcl2水平的升高以及Bax/Bcl2比值的增加表明U1 snRNA过表达可导致细胞凋亡。总之，这些发现表明PS1显著增加U1 snRNA水平，同时伴随着Aβ水平的不利变化、AD相关的tau细胞骨架病理改变以及细胞凋亡。
