Post-transcriptional gene regulation in Alzheimer's Disease

哺乳动物细胞通过改变基因表达模式来响应生理和病理线索。 转录后过程（RNA剪接和成熟，以及mRNA运输，稳定性和翻译）越来越多地被认为是控制基因表达的关键。 RNA调节部分正在进行两项研究，以调查阿尔茨海默病（AD）的转录后基因控制。 通过这些研究，我们试图阐明mRNA序列，RNA结合蛋白和microRNA对调节AD发病机制中关键基因产物表达的贡献。 在过去的资助期间，我们已经鉴定了几种与APP相关的RNA结合蛋白（RBP），并研究了它们对APP表达和mRNA亚细胞定位的影响（Lee et al.，Nature Structural & Molecular Biology，2010）。 我们还鉴定了几种影响神经元功能的microRNAS，包括miR-375（Abdelmohsen等人，摩尔Cell.生物学：2010），并在将神经元DNA修复与细胞周期分布联系起来的研究中合作（Tomashevski et al.，Cell Death and Differentiation，2010）。 正在进行的研究正在评估其他RNA结合蛋白对APP表达的调控，这些蛋白识别富含AU的转录本。 我们还计划研究多态性非编码序列对AD易感基因转录后调控的影响。 晚发性AD的发病机制还不清楚，但连锁研究已将关键的晚发性AD易感基因定位于12号染色体的一个区域。 该染色体区域中的两个基因被假定参与AD：氧化LDL受体1（OLR 1）和转录因子LBP-1c/CP 2/LSF。 鉴于这两个基因具有3UTR多态性，我们正在研究是否具有多态性非翻译序列的等位基因受到不同的转录后调控。

Mammalian cells respond to physiological and pathological cues by implementing changes in gene expression patterns. Post-transcriptional processes (RNA splicing and maturation, as well as mRNA transport, stability and translation) are increasingly recognized as being critically responsible for controlling gene expression. Two studies are underway in the RNA Regulation Section to investigate post-transcriptional gene control in Alzheimers Disease (AD). Through these studies, we seek to elucidate the contribution of mRNA sequences, RNA-binding proteins, and microRNAs towards regulating the expression of critical gene products in AD pathogenesis. During the past funding period, we have identified several RNA-binding proteins (RBPs) that associate with the APP, and have studied their influence on the expression of APP and the subcellular localization of the mRNA (Lee et al., Nature Structural & Molecular Biology, 2010). We also identified several microRNAS that affect neuronal function, including miR-375 (Abdelmohsen et al., Mol. Cell. Biol., 2010), and collaborated in studies linking neuronal DNA repair with cell cycle distribution (Tomashevski et al., Cell Death and Differentiation, 2010). Ongoing studies are assessing the regulation of APP expression by other RNA-binding proteins that recognize AU-rich transcripts. We also plan to investigate the influence of polymorphic noncoding sequences on the post-transcriptional regulation of AD susceptibility genes. The pathogenesis of late-onset AD is not well understood, but linkage studies have mapped critical late-onset AD susceptibility genes to a region in chromosome 12. Two genes in this chromosomal region have been postulated to participate in AD: oxidized LDL-receptor 1 (OLR1) and transcription factor LBP-1c/CP2/LSF. Given that these two genes bear 3UTR polymorphisms, we are investigating if such alleles with polymorphic untranslated sequences are subject to differential post-transcriptional regulation.