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的运输，稳定性和翻译）是至关重要的基因表达调控。 RNA调节部分正在进行几项研究，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，和非编码RNA对AD发病机制的贡献。 在之前的资助期间，我们鉴定了几种与APP mRNA相关的RNA结合蛋白（RBP）（Lee et al. Nature Structural & Molecular Biology，2010）。 与APP mRNA相关的RBP之一HuD被鉴定为胰岛素翻译的主要阻遏物（Lee等人，摩尔Cell，2012），鉴于糖尿病和AD之间有记录的联系，这是一个有趣的发现。 在合作研究中，我们还鉴定了HuR（与HuD相关）在雪旺细胞发育中的重要作用，将这种RBP与AD相关的髓鞘形成缺陷联系起来（Iruarrizaga-Lejarreta et al. J. Neuroscience，2012）。 该项目正在进行的研究正在评估其他限制性商业惯例对APP表达和加工的调节。 我们也在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。 由于这两个基因具有3UTR多态性，我们正在调查，如果这些等位基因多态性的非翻译序列受到差异转录后调控。

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 critically regulate gene expression. Several studies are underway in the RNA Regulation Section to investigate the post-transcriptional gene control that underlies Alzheimer's Disease (AD). Through these studies, we seek to elucidate the contribution of mRNA sequences, RNA-binding proteins, and noncoding RNAs towards AD pathogenesis. During the previous funding period, we identified several RNA-binding proteins (RBPs) that associate with the APP mRNA (Lee et al., Nature Structural & Molecular Biology, 2010). One of the RBPs that associate with APP mRNA, HuD, was identified as being a major repressor of insulin translation (Lee et al., Mol. Cell, 2012), an interesting discovery given the documented links between diabetes and AD. In collaborative studies, we also identified a vital role for HuR (related to HuD) in the development of Schwann cells, linking this RBPs to the defective myelination associated with AD (Iruarrizaga-Lejarreta et al., J. Neuroscience, 2012). Ongoing studies in this Project are assessing the regulation of APP expression and processing by other RBPs. We are also investigating 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. Since these two genes bear 3UTR polymorphisms, we are investigating if such alleles with polymorphic untranslated sequences are subject to differential post-transcriptional regulation.