Post-transcriptional gene regulation in Alzheimer's Disease

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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.