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.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Investigator-Initiated Intramural Research Projects (ZIA)
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National Institute on Aging
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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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