Institute of Biotechnology, Vilnius University, Vilnius, Lithuania.
Institute of Biotechnology, Vilnius University, Vilnius, Lithuania.
Gene. 2021 Jan 15;766:145146. doi: 10.1016/j.gene.2020.145146. Epub 2020 Sep 14.
The removal of introns from mRNA precursors (pre-mRNAs) is an essential step in eukaryotic gene expression. The splicing machinery heavily contributes to biological complexity and especially to the ability of cells to adapt to altered cellular conditions. Hypoxia also plays a key role in the pathophysiology of many diseases, including Alzheimer's disease (AD). In the presented study, we have examined the influence of cellular hypoxia on mRNA splice variant formation from Alzheimer's disease-related Tau and APP genes in brain cells. We have shown that the hypoxic microenvironment influenced the formation of Tau mRNA splice variants, but had no effect on APP mRNA splice variant formation. Additionally, our presented results indicate that splicing factor SRSF1 but not SRSF5 alters the formation of Tau cellular mRNA splice variants in hypoxic cells. Obtained results have also shown that hypoxic brain cells possess enhanced CLK1-4 kinase mRNA levels. This study underlines that cellular hypoxia can influence disease development through changing pre-mRNA splicing.
从 mRNA 前体（pre-mRNAs）中去除内含子是真核基因表达的一个重要步骤。剪接机制为生物复杂性做出了重大贡献，特别是为细胞适应细胞环境改变的能力做出了贡献。缺氧也在许多疾病的病理生理学中起着关键作用，包括阿尔茨海默病（AD）。在本研究中，我们研究了细胞缺氧对脑细胞中与阿尔茨海默病相关的 Tau 和 APP 基因的 mRNA 剪接变体形成的影响。我们表明，缺氧微环境影响 Tau mRNA 剪接变体的形成，但对 APP mRNA 剪接变体的形成没有影响。此外，我们的研究结果表明，剪接因子 SRSF1 而非 SRSF5 改变了缺氧细胞中 Tau 细胞 mRNA 剪接变体的形成。获得的结果还表明，缺氧脑细胞具有增强的 CLK1-4 激酶 mRNA 水平。本研究强调，细胞缺氧可以通过改变 pre-mRNA 剪接来影响疾病的发展。
