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 have identified two RNA-binding proteins that regulate the translation of APP by binding to the coding region of APP mRNA and modulate its subcellular localization. A report describing our findings was recently submitted for publication. Another RBP that interacts with the APP mRNA (the RBP HuD) was recently identified as being regulated by microRNA miR-375 (Abdelmohsen et al., Mol. Cell. Biol. 2010). 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. In collaboration with Dr. I.I. Kruman, we investigated a feature of AD pathogenesis, the impaired ability of neurons to respond to macromolecular damage. A recent report describes that cyclin C is necessary for activation of nonhomologous end joining DNA repair in postmitotic neurons (Tomashevski et al., Cell Death Diff. 2010).
| Idda, M Laura; Munk, Rachel; Abdelmohsen, Kotb et al. (2018) Noncoding RNAs in Alzheimer's disease. Wiley Interdiscip Rev RNA 9: |
| Grammatikakis, Ioannis; Abdelmohsen, Kotb; Gorospe, Myriam (2017) Posttranslational control of HuR function. Wiley Interdiscip Rev RNA 8: |
| Grammatikakis, Ioannis; Zhang, Peisu; Mattson, Mark P et al. (2016) The long and the short of TRF2 in neurogenesis. Cell Cycle 15:3026-3032 |
| Grammatikakis, Ioannis; Zhang, Peisu; Panda, Amaresh C et al. (2016) Alternative Splicing of Neuronal Differentiation Factor TRF2 Regulated by HNRNPH1/H2. Cell Rep 15:926-934 |
| Grammatikakis, Ioannis; Gorospe, Myriam (2016) Identification of neural stem cell differentiation repressor complex Pnky-PTBP1. Stem Cell Investig 3:10 |
| Ahmad, Muzammil; Xue, Yutong; Lee, Seung Kyu et al. (2016) RNA topoisomerase is prevalent in all domains of life and associates with polyribosomes in animals. Nucleic Acids Res 44:6335-49 |
| Uren, Philip J; Vo, Dat T; de Araujo, Patricia Rosa et al. (2015) RNA-Binding Protein Musashi1 Is a Central Regulator of Adhesion Pathways in Glioblastoma. Mol Cell Biol 35:2965-78 |
| Zhang, Peisu; Abdelmohsen, Kotb; Liu, Yong et al. (2015) Novel RNA- and FMRP-binding protein TRF2-S regulates axonal mRNA transport and presynaptic plasticity. Nat Commun 6:8888 |
| Yoon, Je-Hyun; Gorospe, Myriam (2014) Ribonucleoprotein therapy in Alzheimer's disease? Aging (Albany NY) 6:428-9 |
| Hutchison, Emmette R; Kawamoto, Elisa M; Taub, Dennis D et al. (2013) Evidence for miR-181 involvement in neuroinflammatory responses of astrocytes. Glia 61:1018-28 |
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