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Hum Mol Genet. 2014 Dec 1;23(23):6318-31. doi: 10.1093/hmg/ddu350. Epub 2014 Jul 4.

SMN regulates axonal local translation via miR-183/mTOR pathway.

Author information

1
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.
2
Department of Neurology, The F. M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
3
Institute of Human Genetics, Institute for Genetics and.
4
Center for Motor Neuron Biology and Disease, Department of Pathology and Cell Biology and.
5
Institute of Human Genetics, Institute for Genetics and, Center of Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
6
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.
7
Neuroscience Research Institute, University of California at Santa Barbara, Santa Barbara, CA 93106, USA.
8
Genzyme, a Sanofi Company, Framingham, MA 01701, USA.
9
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.
10
Department of Neurology, The F. M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA, mustafa.sahin@childrens.harvard.edu.

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.

PMID:
25055867
PMCID:
PMC4271102
DOI:
10.1093/hmg/ddu350
[Indexed for MEDLINE]
Free PMC Article
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