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.? ? The first set of studies is aimed at investigating the post-transcriptional regulation of amyloid precursor protein (APP) expression. APP is a cell-surface protein whose cleavage can lead to the generation of small extracellular peptides (Abeta or amyloid-beta peptides) which are involved in AD. Amyloidogenic cells overexpress APP mRNA, which in turn enhances the production of toxic Abeta peptides leading to their accumulation and deposit in the brains of patients with AD. Given earlier reports that APP expression is critically regulated by altered mRNA stability and protein biosynthesis, we are seeking to systematically identify the RNA-binding proteins and microRNAs that associate with the APP mRNA and influence their half-life and translation. Using a number of in vitro and in vivo approaches, we have began to assess the association of APP mRNA with known RNA-binding proteins that recognize AU-rich transcripts, including HuR, AUF1, TTP, TIA-1, TIAR, KSRP, FMRP, NF-90, hnRNP A1, and BRF1. We plan to use affinity purification methods to identify additional proteins that form complexes with the APP mRNA. The functional consequences of these ribonucleoprotein associations will be subsequently tested in cell lines relevant to AD. Using similar methodologies, we have began a search to identify microRNAs that may regulate APP mRNA half-life and translation rate.? ? Second, we 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.
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