Several studies are underway in the RNA Regulation Section to investigate the RBPs and ncRNAs that influence neuronal physiology and pathology, with particular emphasis on neurodegeneration. During this review period, we have studied the role of several RBPs and ncRNAs implicated in Alzheimers disease (AD) as well as other pathologies of the nervous system. We previously reported that the levels of amyloid precursor protein (APP), which is cleaved to release the Alzheimers disease hallmark peptide Abeta, was regulated by RBPs FMRP (fragile X mental retardation protein) and hnRNP C (heterogeneous nuclear ribonucleoprotein C) (Lee et al., Nature Structural and Molecular Biology, 2010), as well as by the RBP HuD (Kang et al., Cell Reports 2014) led us to propose that HuD jointly promotes the production of APP and the cleavage of its amyloidogenic fragment, Abeta. During this funding period, we collaborated with Dr. M. Mattsons in studies that uncovered that the nontelomeric isoform of telomere repeat-binding factor 2 (TRF2-S) is a novel RBP that regulates axonal plasticity. TRF2-S interacts directly with target mRNAs to facilitate their axonal delivery in a process that is antagonized by fragile X mental retardation protein. Interestingly, FMRP blocks the assembly of TRF2-S-mRNA complexes, and accordingly overexpressing TRF2-S and silencing FMRP promotes mRNA entry to axons, and enhances axonal outgrowth and neurotransmitter release from presynaptic terminals. These findings suggest a function for TRF2-S in an axonal mRNA localization pathway that may regulate local protein synthesis by counteracting FMRP-mediated inhibition, thereby enhancing axonal outgrowth and neurotransmitter release (Zhang et al., 2015). More recently, we identified heterogeneous nuclear ribonucleoproteins H1 and H2(HNRNPH) as RBPs specifically capable of interacting with the spliced RNA segment (exon 7) of Trf2 pre-mRNA. HNRNPH proteins prevent the production of the short isoform of Trf2 mRNA, as HNRNPH silencing selectively elevates TRF2-S levels. Accordingly, HNRNPH levels decline while TRF2-S levels increase during neuronal differentiation. Using CRISPR/Cas9-mediated deletion of hnRNPH2 we found a selective acceleration of the NGF-triggered differentiation of rat pheochromocytoma cells into neurons. We propose that HNRNPH is a splicing regulator of Trf2 pre-mRNA that prevents the expression of TRF2-S, a factor implicated in neuronal differentiation (Grammatikakis et al., Cell Reports, 2016). A follow-up review discussed the distinct nuclear and cytoplasmic functions of TRF2 (Grammatikakis et al., Cell Cycle 2016). Additional studies in collaboration with members of the Laboratory of Genetics and Genomics characterized the phylogeny of topoisomerase 3 beta (Ahmad et al., Nucleic Acids Research 2016), while other collaborative efforts were devoted to identifying the role of the RBP Musashi in the brain malignancy glioblastoma (Uren et al., Molecular and Cellular Biology, 2015). Finally, we discussed the role of a lncRNA, Pnky, which influenced neural stem cell differentiation by binding to PTBP1 (Grammatikakis et al., Stem Cell Investigation, 2016).
| 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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