Post-transcriptional gene regulation in Alzheimer's Disease

National Institute On Aging

Investigators

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Abstract

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.