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

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 theSMN ortholog, SMN-1, causes NMJ defects. We found that increased levels of theGemin3 ortholog, MEL-46, ameliorates these defects. Increased MEL-46 levels also restored perturbed microRNA (miR-2) function inanimals. We determined that miR-2 regulates expression of theM2 muscarinic receptor (m2R) ortholog, GAR-2. GAR-2 loss amelioratedandsynaptic 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 functionMEL-46 misregulation, followed by increased m2R expression, and neuronal dysfunction in SMA.