title: Valproic acid mediates miR-124 to down-regulate a novel protein target, GNAI1.
abstract: Valproic acid (VPA) is an anti-convulsant drug that is recently shown to have neuroregenerative therapeutic actions. In this study, we investigate the underlying molecular mechanism of VPA and its effects on Bdnf transcription through microRNAs (miRNAs) and their corresponding target proteins. Using in silico algorithms, we predicted from our miRNA microarray and iTRAQ data that miR-124 is likely to target at guanine nucleotide binding protein alpha inhibitor 1 (GNAI1), an adenylate cyclase inhibitor. With the reduction of GNAI1 mediated by VPA, the cAMP is enhanced to increase Bdnf expression. The levels of GNAI1 protein and Bdnf mRNA can be manipulated with either miR-124 mimic or inhibitor. In summary, we have identified a novel molecular mechanism of VPA that induces miR-124 to repress GNAI1. The implication of miR-124→GNAI1→BDNF pathway with valproic acid treatment suggests that we could repurpose an old drug, valproic acid, as a clinical application to elevate neurotrophin levels in treating neurodegenerative diseases.
authors.affiliation: Neuroepigenetics Laboratory, Singapore Institute for Clinical Sciences, Agency for Science and Technology (A*STAR), Singapore.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Oikawa
authors.affiliation: School of Pharmaceutical Science and Technology, Tianjin University, China; School of Computing, National University of Singapore, Singapore.
authors.forename: Wilson W B
authors.initials: WW
authors.lastname: Goh
authors.affiliation: Neuroepigenetics Laboratory, Singapore Institute for Clinical Sciences, Agency for Science and Technology (A*STAR), Singapore.
authors.forename: Vania K J
authors.initials: VK
authors.lastname: Lim
authors.affiliation: School of Computing, National University of Singapore, Singapore.
authors.forename: Limsoon
authors.initials: L
authors.lastname: Wong
authors.affiliation: Neuroepigenetics Laboratory, Singapore Institute for Clinical Sciences, Agency for Science and Technology (A*STAR), Singapore; Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. Electronic address: phcsngj@nus.edu.sg.
authors.forename: Judy C G
authors.initials: JC
authors.lastname: Sng
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D003198:Computer Simulation; D000242:Cyclic AMP / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000096:biosynthesis*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000096:biosynthesis / Q000187:drug effects* / Q000235:genetics; D008969:Molecular Sequence Data; D014635:Valproic Acid / Q000494:pharmacology*; D014793:Visual Cortex / Q000187:drug effects / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C579276:Gnai1 protein, mouse; D035683:MicroRNAs; C540079:Mirn124 microRNA, mouse; D014635:Valproic Acid; D000242:Cyclic AMP; D019206:GTP-Binding Protein alpha Subunits, Gi-Go
keywords: Adenylate cyclase inhibitor; Bdnf; MicroRNAs; Visual cortices; iTRAQ