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Elife. 2017 May 2;6. pii: e20752. doi: 10.7554/eLife.20752.

Decreased microRNA levels lead to deleterious increases in neuronal M2 muscarinic receptors in Spinal Muscular Atrophy models.

Author information

1
Department of Neuroscience, Brown University, Providence, United States.
2
Institute of Human Genetics, University of Cologne, Cologne, Germany.
3
Brown Institute for Brain Science, Providence, United States.

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.

KEYWORDS:

C. elegans; GAR-2; Gemin3; SMA; SMN; m2R; microRNA; neuroscience

PMID:
28463115
PMCID:
PMC5413352
DOI:
10.7554/eLife.20752
[Indexed for MEDLINE]
Free PMC Article

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