Journal
HUMAN MOLECULAR GENETICS
Volume 23, Issue 23, Pages 6318-6331Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddu350
Keywords
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Funding
- Slaney Family Fund
- Whitehall Foundation
- Boston Children's Hospital (BCH) Translational Research Program
- BCH Intellectual and Developmental Disabilities Research Center [P30 HD18655]
- Harvard NeuroDiscovery Center
- Hearst Foundation
- Developmental Neurology Training Grant [T32 NS007473]
- National Science Foundation [PHY05-51164]
- Deutsche Forschungsgemeinschaft [Wi945-14/1]
- EU [2012-305121]
- CMMC [C11]
- SMA-Europe
- fSMA
- MDA
- [R01 NS057482]
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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.
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