MicroRNA 486 is a potentially novel target for the treatment of spinal cord injury

• Published in: Brain (London, England : 1878) England : 1878), 2012-04, Vol.135 (Pt 4), p.1237-1252
• Main Authors: Jee, Min Ki, Jung, Jin Sun, Choi, Jee In, Jang, Jin Ah, Kang, Kyung Sun, Im, Young Bin, Kang, Soo Kyung
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - metabolism; Analysis of Variance; Animal models; Animals; Apoptosis; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - metabolism; Biological and medical sciences; Brain injury; Caspase 3 - metabolism; Cells, Cultured; Conserved sequence; Cytokines - metabolism; Disease Models, Animal; Female; Gene expression; Gene Expression Regulation - drug effects; Gene Expression Regulation - physiology; Glial Fibrillary Acidic Protein - metabolism; Glutathione peroxidase; Inflammation; Injuries of the nervous system and the skull. Diseases due to physical agents; Medical sciences; Mice; Mice, Inbred ICR; MicroRNAs - genetics; MicroRNAs - metabolism; miRNA; Motor Activity - drug effects; Motor neurons; Motor Neurons - drug effects; Motor Neurons - metabolism; Myelin Basic Protein - metabolism; Nerve Degeneration - drug therapy; Nerve Degeneration - etiology; Nerve Degeneration - metabolism; Neural Stem Cells - drug effects; Neural Stem Cells - metabolism; Neurodegeneration; Neurofilament Proteins - metabolism; Neurology; Neuroprotection; Nitric Oxide Synthase Type II - metabolism; Nitric Oxide Synthase Type III - metabolism; Oligodeoxyribonucleotides, Antisense - pharmacology; Peroxidase - metabolism; Reactive oxygen species; Reactive Oxygen Species - metabolism; Recovery of Function - drug effects; Recovery of Function - genetics; Recovery of Function - physiology; Regulatory sequences; RNA, Small Interfering - pharmacology; Spinal Cord Injuries - metabolism; Spinal Cord Injuries - physiopathology; Spinal Cord Injuries - therapy; Spinal cord injury; Time Factors; Translation; Traumas. Diseases due to physical agents
• ISSN: 0006-8950; 1460-2156
• DOI: 10.1093/brain/aws047

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.