RRC ID 51385
Author O'Hern PJ, do Carmo G Gonçalves I, Brecht J, López Soto EJ, Simon J, Chapkis N, Lipscombe D, Kye MJ, Hart AC.
Title Decreased microRNA levels lead to deleterious increases in neuronal M2 muscarinic receptors in Spinal Muscular Atrophy models.
Journal Elife
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.
Volume 6
Published 2017-5-2
DOI 10.7554/eLife.20752
PII e20752
PMID 28463115
PMC PMC5413352
MeSH Animals Caenorhabditis elegans* Caenorhabditis elegans Proteins / metabolism* DEAD-box RNA Helicases / metabolism Disease Models, Animal MicroRNAs / metabolism* Muscular Atrophy, Spinal / physiopathology* Receptor, Muscarinic M2 / analysis* Survival of Motor Neuron 1 Protein / metabolism*
IF 7.08
Times Cited 13
C.elegans tm1739