title: SMN regulates axonal local translation via miR-183/mTOR pathway.
abstract: Reduced expression of SMN protein causes spinal muscular atrophy (SMA), a neurodegenerative disorder leading to motor neuron dysfunction and loss. However, the molecular mechanisms by which SMN regulates neuronal dysfunction are not fully understood. Here, we report that reduced SMN protein level alters miRNA expression and distribution in neurons. In particular, miR-183 levels are increased in neurites of SMN-deficient neurons. We demonstrate that miR-183 regulates translation of mTor via direct binding to its 3' UTR. Interestingly, local axonal translation of mTor is reduced in SMN-deficient neurons, and this can be recovered by miR-183 inhibition. Finally, inhibition of miR-183 expression in the spinal cord of an SMA mouse model prolongs survival and improves motor function of Smn-mutant mice. Together, these observations suggest that axonal miRNAs and the mTOR pathway are previously unidentified molecular mechanisms contributing to SMA pathology.
authors: Department of Neurology, The F. M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA, Institute of Human Genetics, Institute for Genetics and.
authors: Min Jeong
authors: MJ
authors: Kye
authors: Department of Neurology, The F. M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
authors: Emily D
authors: ED
authors: Niederst
authors: Department of Neurology, The F. M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
authors: Mary H
authors: MH
authors: Wertz
authors: Institute of Human Genetics, Institute for Genetics and.
authors: Inês do Carmo G
authors: Ido C
authors: Gonçalves
authors: Department of Neurology, The F. M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
authors: Bikem
authors: B
authors: Akten
authors: Center for Motor Neuron Biology and Disease, Department of Pathology and Cell Biology and.
authors: Katarzyna Z
authors: KZ
authors: Dover
authors: Institute of Human Genetics, Institute for Genetics and, Center of Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
authors: Miriam
authors: M
authors: Peters
authors: Institute of Human Genetics, Institute for Genetics and, Center of Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
authors: Markus
authors: M
authors: Riessland
authors: Kavli Institute for Theoretical Physics and, Neuroscience Research Institute, University of California at Santa Barbara, Santa Barbara, CA 93106, USA, Cell Biology and Biophysics Unit, European Molecular Biology Laboratory, 69117, Heidelberg, Germany and.
authors: Pierre
authors: P
authors: Neveu
authors: Institute of Human Genetics, Institute for Genetics and, Center of Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
authors: Brunhilde
authors: B
authors: Wirth
authors: Neuroscience Research Institute, University of California at Santa Barbara, Santa Barbara, CA 93106, USA.
authors: Kenneth S
authors: KS
authors: Kosik
authors: Genzyme, a Sanofi Company, Framingham, MA 01701, USA.
authors: S Pablo
authors: SP
authors: Sardi
authors: Center for Motor Neuron Biology and Disease, Department of Pathology and Cell Biology and, Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA.
authors: Umrao R
authors: UR
authors: Monani
authors: Genzyme, a Sanofi Company, Framingham, MA 01701, USA.
authors: Marco A
authors: MA
authors: Passini
authors: Department of Neurology, The F. M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA, mustafa.sahin@childrens.harvard.edu.
authors: Mustafa
authors: M
authors: Sahin
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D001369:Axons / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009134:Muscular Atrophy, Spinal / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism; D061251:Primary Cell Culture; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D020413:3' Untranslated Regions; C584645:MIRN183 microRNA, rat; D035683:MicroRNAs; D012333:RNA, Messenger; C526473:Smn1 protein, rat; D055533:Survival of Motor Neuron 1 Protein; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases