title: MicroRNA 486 is a potentially novel target for the treatment of spinal cord injury.
abstract: MicroRNAs have been shown to effectively regulate gene expression at the translational level. Recently, we identified novel microRNAs that were upregulated in a mouse model of spinal cord injury. Among those, we have focused on microRNA 486, which directly represses NeuroD6 expression through a conserved sequence in its untranslated region. We correlated the overexpression of microRNA 486 in motor neurons with a poor outcome due to progressive neurodegeneration and a pathophysiology that is mediated by reactive oxygen species. The expression of microRNA 486 was induced by reactive oxygen species that were produced by inflammatory factors, and reactive oxygen species were accumulated in response to the knockdown of NeuroD6, which enhances the downregulation of glutathione peroxidase 3 and thioredoxin-like 1 after traumatic spinal cord injury. NeuroD6 directly bound to regulatory regions of thioredoxin-like 1 and glutathione peroxidase 3 in motor neurons and activated their expression, which promoted reactive oxygen species scavenging. Moreover, knocking down microRNA 486 induced the expression of NeuroD6, which effectively ameliorated the spinal cord injury and allowed the mice to recover motor function. The infusion of exogenic NeuroD6 in spinal cord injury lesions effectively blocked apoptosis by reactivating thioredoxin-like 1 and glutathione peroxidase 3, which was accompanied by a recovery of motor function. Collectively, these findings have identified a novel microRNA in spinal cord injury lesions called microRNA 486, demonstrating a new role for NeuroD6 in neuroprotection, and suggest a potential therapeutic target for spinal cord injuries.
authors.affiliation: Laboratory of Stem Cell Biology, Department of Biotechnology, College of Veterinary Medicine, Seoul National University, Seoul 151-742, Korea.
authors.forename: Min Ki
authors.initials: MK
authors.lastname: Jee
authors.forename: Jin Sun
authors.initials: JS
authors.lastname: Jung
authors.forename: Jee In
authors.initials: JI
authors.lastname: Choi
authors.forename: Jin Ah
authors.initials: JA
authors.lastname: Jang
authors.forename: Kyung Sun
authors.initials: KS
authors.lastname: Kang
authors.forename: Young Bin
authors.initials: YB
authors.lastname: Im
authors.forename: Soo Kyung
authors.initials: SK
authors.lastname: Kang
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009043:Motor Activity / Q000187:drug effects; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism; D004676:Myelin Basic Protein / Q000378:metabolism; D009410:Nerve Degeneration / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D058953:Neural Stem Cells / Q000187:drug effects / Q000378:metabolism; D016900:Neurofilament Proteins / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D009195:Peroxidase / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D020127:Recovery of Function / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D013119:Spinal Cord Injuries / Q000378:metabolism* / Q000503:physiopathology / Q000628:therapy*; D013997:Time Factors
chemical_list: D000255:Adenosine Triphosphate; D051792:Basic Helix-Loop-Helix Proteins; D053148:Caspase 3; D016207:Cytokines; D005904:Glial Fibrillary Acidic Protein; D035683:MicroRNAs; D004676:Myelin Basic Protein; D016900:Neurofilament Proteins; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D020319:Oligodeoxyribonucleotides, Antisense; D009195:Peroxidase; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C490554:Neurod6 protein, rat; C050934:neurofilament protein 150