Kye, Min Jeong ORCID: 0000-0002-1323-7256, Niederst, Emily D., Wertz, Mary H., Goncalves, Ines do Carmo G., Akten, Bikem, Dover, Katarzyna Z., Peters, Miriam, Riessland, Markus ORCID: 0000-0003-2592-5045, Neveu, Pierre ORCID: 0000-0003-4939-3418, Wirth, Brunhilde ORCID: 0000-0003-4051-5191, Kosik, Kenneth S., Sardi, S. Pablo, Monani, Umrao R., Passini, Marco A. and Sahin, Mustafa (2014). SMN regulates axonal local translation via miR-183/mTOR pathway. Hum. Mol. Genet., 23 (23). S. 6318 - 6332. OXFORD: OXFORD UNIV PRESS. ISSN 1460-2083

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Kye, Min JeongUNSPECIFIEDorcid.org/0000-0002-1323-7256UNSPECIFIED
Niederst, Emily D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wertz, Mary H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Goncalves, Ines do Carmo G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Akten, BikemUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dover, Katarzyna Z.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peters, MiriamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Riessland, MarkusUNSPECIFIEDorcid.org/0000-0003-2592-5045UNSPECIFIED
Neveu, PierreUNSPECIFIEDorcid.org/0000-0003-4939-3418UNSPECIFIED
Wirth, BrunhildeUNSPECIFIEDorcid.org/0000-0003-4051-5191UNSPECIFIED
Kosik, Kenneth S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sardi, S. PabloUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Monani, Umrao R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Passini, Marco A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sahin, MustafaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-422500
DOI: 10.1093/hmg/ddu350
Journal or Publication Title: Hum. Mol. Genet.
Volume: 23
Number: 23
Page Range: S. 6318 - 6332
Date: 2014
Publisher: OXFORD UNIV PRESS
Place of Publication: OXFORD
ISSN: 1460-2083
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
SPINAL MUSCULAR-ATROPHY; MOTOR-NEURON PROTEIN; MESSENGER-RNA; GENE-PRODUCT; SYMPATHETIC NEURONS; CORTICAL-NEURONS; GROWTH CONES; SURVIVAL; COMPLEX; DISEASEMultiple languages
Biochemistry & Molecular Biology; Genetics & HeredityMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/42250

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