Journal Article

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

Kye, Min Jeong, Lipscombe, Diane, Brecht, Johanna, do Carmo G. Gonçalves, Inês, Simon, Jonah, Hart, Anne C, O'Hern, Patrick J, López Soto, Eduardo Javier, Chapkis, Natalie

2017

Overview

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. Spinal muscular atrophy is a genetic disease that causes muscles to gradually weaken. In people with the disease, the nerve cells that control the movement of muscles – called motor neurons – deteriorate over time, hindering the person’s mobility and shortening their life expectancy. Spinal muscular atrophy is usually caused by genetic faults affecting a protein called SMN (which is short for “Survival of motor neuron”) and recent research suggested that disrupting this protein alters the function of short pieces of genetic material called microRNAs. However, the precise role that microRNAs play in the disease and their connection to the SMN protein was not clear. MicroRNAs interfere with the production of proteins by disrupting molecules called messenger RNAs, which are temporary strings of genetic code that carry the instructions for making protein. By disrupting messenger RNAs, microRNAs can delay or halt the production of specific proteins. This is an important part of the normal behavior of a cell, but disturbing the activity of microRNAs can lead to an unwanted rise or fall in crucial proteins. O’Hern et al. made use of engineered nematode worms and mice that share genetic features with spinal muscular atrophy patients, including disruption of the gene responsible for producing the SMN protein. These animal models of the disease were used to examine the relationship between decreased SMN levels and microRNAs in motor neurons. The experiments showed that reduced SMN activity affects a specific microRNA, which in turn causes motor neurons to produce more of a protein called m2R. This protein is a receptor for a molecule, called acetylcholine, which motor neurons use to send signals to muscle cells. Increased m2R may be detrimental to motor neurons. As such, O’Hern et al. decreased m2R protein activity to determine whether this could reverse the defects in motor neurons that arise in the animal models of the disease. Indeed, blocking this receptor rescued some of the defects seen in the animal models, supporting the link to spinal muscular atrophy. Several treatments that block m2R are already available to treat other conditions. As such, the next step is to determine whether these existing treatments are able to protect mice models of spinal muscular atrophy against muscle deterioration or increase their lifespan. If successful, this could open new avenues for the development of treatments in people.

• Publisher: eLife Science Publications, Ltd,eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd
• Subject: Acetylcholine receptors (muscarinic) / Animal models / Animals / Caenorhabditis elegans / Caenorhabditis elegans Proteins - metabolism / DEAD-box RNA Helicases - metabolism / Defects / Disease Models, Animal / GAR-2 / Gemin3 / Gene expression / Genetic aspects / Health aspects / m2R / Measurement / MicroRNA / MicroRNAs / MicroRNAs - metabolism / miRNA / mRNA / Muscarinic receptors / Muscular Atrophy, Spinal - physiopathology / Mutation / Neuromuscular diseases / Neuromuscular junctions / Neuroscience / Paralysis / Physiological aspects / Properties / Proteins / Receptor, Muscarinic M2 - analysis / Rodents / SMA / SMN / SMN protein / Spinal muscular atrophy / Statistical analysis / Survival of Motor Neuron 1 Protein - metabolism