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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAAG000518-08
Application #
8552418
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
8
Fiscal Year
2012
Total Cost
$354,616
Indirect Cost
Name
National Institute on Aging
Department
Type
DUNS #
City
State
Country
Zip Code
Grammatikakis, Ioannis; Zhang, Peisu; Panda, Amaresh C et al. (2016) Alternative Splicing of Neuronal Differentiation Factor TRF2 Regulated by HNRNPH1/H2. Cell Rep 15:926-34
Grammatikakis, Ioannis; Abdelmohsen, Kotb; Gorospe, Myriam (2016) Posttranslational control of HuR function. Wiley Interdiscip Rev RNA :
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
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
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
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
Xu, Dongyi; Shen, Weiping; Guo, Rong et al. (2013) Top3β is an RNA topoisomerase that works with fragile X syndrome protein to promote synapse formation. Nat Neurosci 16:1238-47
Park, Young Mi; Hwang, Su Jin; Masuda, Kiyoshi et al. (2012) Heterogeneous nuclear ribonucleoprotein C1/C2 controls the metastatic potential of glioblastoma by regulating PDCD4. Mol Cell Biol 32:4237-44

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