title: Neuronal ELAVL proteins utilize AUF-1 as a co-partner to induce neuron-specific alternative splicing of APP.
abstract: Aβ peptide that accumulates in Alzheimer's disease brain, derives from proteolytic processing of the amyloid precursor protein (APP) that exists in three main isoforms derived by alternative splicing. The isoform APP695, lacking exons 7 and 8, is predominately expressed in neurons and abnormal neuronal splicing of APP has been observed in the brain of patients with Alzheimer's disease. Herein, we demonstrate that expression of the neuronal members of the ELAVL protein family (nELAVLs) correlate with APP695 levels in vitro and in vivo. Moreover, we provide evidence that nELAVLs regulate the production of APP695; by using a series of reporters we show that concurrent binding of nELAVLs to sequences located both upstream and downstream of exon 7 is required for its skipping, whereas nELAVL-binding to a highly conserved U-rich sequence upstream of exon 8, is sufficient for its exclusion. Finally, we report that nELAVLs block APP exon 7 or 8 definition by reducing the binding of the essential splicing factor U2AF65, an effect facilitated by the concurrent binding of AUF-1. Our study provides new insights into the regulation of APP pre-mRNA processing, supports the role for nELAVLs as neuron-specific splicing regulators and reveals a novel function of AUF1 in alternative splicing.
authors.affiliation: Center for Basic Research, Biomedical Research Foundation Academy of Athens, 4 Soranou Efesiou str, 11527, Athens Greece.
authors.forename: Apostolia
authors.initials: A
authors.lastname: Fragkouli
authors.affiliation: Center for Basic Research, Biomedical Research Foundation Academy of Athens, 4 Soranou Efesiou str, 11527, Athens Greece.
authors.forename: Pelagia
authors.initials: P
authors.lastname: Koukouraki
authors.affiliation: Hellenic Pasteur Institute, 127 Vasilissis Sofias Avenue, 11521 Athens, Greece.|DIANA-Lab, Department of Electrical &Computer Engineering, University of Thessaly, 38221 Volos, Greece.
authors.forename: Ioannis S
authors.initials: IS
authors.lastname: Vlachos
authors.affiliation: Hellenic Pasteur Institute, 127 Vasilissis Sofias Avenue, 11521 Athens, Greece.|DIANA-Lab, Department of Electrical &Computer Engineering, University of Thessaly, 38221 Volos, Greece.
authors.forename: Maria D
authors.initials: MD
authors.lastname: Paraskevopoulou
authors.affiliation: Hellenic Pasteur Institute, 127 Vasilissis Sofias Avenue, 11521 Athens, Greece.|DIANA-Lab, Department of Electrical &Computer Engineering, University of Thessaly, 38221 Volos, Greece.
authors.forename: Artemis G
authors.initials: AG
authors.lastname: Hatzigeorgiou
authors.affiliation: Center for Basic Research, Biomedical Research Foundation Academy of Athens, 4 Soranou Efesiou str, 11527, Athens Greece.
authors.forename: Epaminondas
authors.initials: E
authors.lastname: Doxakis
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D001921:Brain / Q000473:pathology; D000067777:ELAV-Like Protein 2 / Q000235:genetics; D005786:Gene Expression Regulation; D006367:HeLa Cells; D000081035:Heterogeneous Nuclear Ribonucleoprotein D0; D034502:Heterogeneous-Nuclear Ribonucleoprotein D / Q000235:genetics*; D006801:Humans; D005810:Multigene Family / Q000235:genetics; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000235:genetics*; D011485:Protein Binding; D020033:Protein Isoforms / Q000235:genetics; D012322:RNA Precursors / Q000235:genetics; D000072668:Splicing Factor U2AF / Q000235:genetics; D000074019:T-Cell Intracellular Antigen-1 / Q000235:genetics
chemical_list: D016564:Amyloid beta-Protein Precursor; D000067777:ELAV-Like Protein 2; C086811:ELAVL2 protein, human; C000630986:HNRNPD protein, human; D000081035:Heterogeneous Nuclear Ribonucleoprotein D0; D034502:Heterogeneous-Nuclear Ribonucleoprotein D; D010446:Peptide Fragments; D020033:Protein Isoforms; D012322:RNA Precursors; D000072668:Splicing Factor U2AF; D000074019:T-Cell Intracellular Antigen-1; C071558:TIA1 protein, human; C093597:amyloid beta-protein precursor 695 (18-38)