Universität zu Köln

O'Hern, Patrick J., Goncalves, Ines do Carmo G., Brecht, Johanna, Soto, Eduardo Javier Lopes, Simon, Jonah, Chapkis, Natalie ORCID: 0000-0001-5158-0779, Lipscombe, Diane, Kye, Min Jeong ORCID: 0000-0002-1323-7256 and Hart, Anne C. (2017). Decreased microRNA levels lead to deleterious increases in neuronal M2 muscarinic receptors in Spinal Muscular Atrophy models. eLife, 6. CAMBRIDGE: ELIFE SCIENCES PUBLICATIONS LTD. ISSN 2050-084X

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Abstract

Spinal Muscular Atrophy (SMA) is caused by diminished Survival of Motor Neuron (SMN) protein, leading to neuromuscular junction (NMJ) dysfunction and spinal motor neuron (MN) loss. Here, we report that reduced SMN function impacts the action of a pertinent microRNA and its mRNA target in MNs. Loss of the C. elegans SMN ortholog, SMN-1, causes NMJ defects. We found that increased levels of the C. elegans Gemin3 ortholog, MEL-46, ameliorates these defects. Increased MEL-46 levels also restored perturbed microRNA (miR-2) function in smn-1(lf) animals. We determined that miR-2 regulates expression of the C. elegans M2 muscarinic receptor (m2R) ortholog, GAR-2. GAR-2 loss ameliorated smn-1(lf) and mel-46(lf) synaptic defects. In an SMA mouse model, m2R levels were increased and pharmacological inhibition of m2R rescued MN process defects. Collectively, these results suggest decreased SMN leads to defective microRNA function via MEL-46 misregulation, followed by increased m2R expression, and neuronal dysfunction in SMA.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code O'Hern, Patrick J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Goncalves, Ines do Carmo G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Brecht, Johanna UNSPECIFIED UNSPECIFIED UNSPECIFIED Soto, Eduardo Javier Lopes UNSPECIFIED UNSPECIFIED UNSPECIFIED Simon, Jonah UNSPECIFIED UNSPECIFIED UNSPECIFIED Chapkis, Natalie UNSPECIFIED orcid.org/0000-0001-5158-0779 UNSPECIFIED Lipscombe, Diane UNSPECIFIED UNSPECIFIED UNSPECIFIED Kye, Min Jeong UNSPECIFIED orcid.org/0000-0002-1323-7256 UNSPECIFIED Hart, Anne C. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-231390
DOI:	10.7554/eLife.20752
Journal or Publication Title:	eLife
Volume:	6
Date:	2017
Publisher:	ELIFE SCIENCES PUBLICATIONS LTD
Place of Publication:	CAMBRIDGE
ISSN:	2050-084X
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language MOTOR-NERVE TERMINALS; DEAD-BOX PROTEIN; CAENORHABDITIS-ELEGANS; MESSENGER-RNA; SMN COMPLEX; C-ELEGANS; SYNAPTIC-TRANSMISSION; CHOLINERGIC INTERNEURONS; ACETYLCHOLINE-RECEPTOR; NEUROMUSCULAR-JUNCTION Multiple languages Biology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/23139