Open AccessSMN regulates axonal local translation via miR-183/mTOR pathway
Author(s) -
Min Jeong Kye,
Emily Niederst,
Mary H. Wertz,
Inês do Carmo G. Gonçalves,
Bikem Akten,
Katarzyna Dover,
Miriam Peters,
Markus Rießland,
Pierre Neveu,
Brunhilde Wirth,
Kenneth S. Kosik,
S. Pablo Sardi,
Umrao R. Monani,
Marco A. Passini,
Mustafa Şahin
Publication year - 2014
Publication title -
human molecular genetics online/human molecular genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.811
H-Index - 276
eISSN - 1460-2083
pISSN - 0964-6906
DOI - 10.1093/hmg/ddu350
Subject(s) - sma* , biology , spinal muscular atrophy , pi3k/akt/mtor pathway , translation (biology) , microrna , motor neuron , neuroscience , microbiology and biotechnology , spinal cord , signal transduction , messenger rna , gene , genetics , mathematics , combinatorics
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.