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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.
Highlights
Spinal Muscular Atrophy (SMA) is an autosomal recessive neurodegenerative disease and the leading genetic cause of infant death in the US (Cusin et al, 2003; Pearn, 1978)
Homozygous loss of smn-1 or mel-46 results in lethality (Briese et al, 2009; Miguel-Aliaga et al, 1999), but maternal loading of smn-1 or mel-46 messenger RNA (mRNA) and protein allows many homozygous, loss of function animals to survive into the last larval stage, called L4 (Miguel-Aliaga et al, 1999; Minasaki et al, 2009)
Like smn-1 loss in L4 stage animals, we found that mel-46 homozygous loss of function animals had severely decreased pharyngeal pumping rates
Summary
Spinal Muscular Atrophy (SMA) is an autosomal recessive neurodegenerative disease and the leading genetic cause of infant death in the US (Cusin et al, 2003; Pearn, 1978). SMA is caused by homozygous deletion or mutation of the SMN1 (Survival Motor Neuron 1) gene, resulting in reduced Survival of Motor Neuron (SMN) protein levels (Lefebvre et al, 1995). SMN expression is ubiquitous, but essential for motor neuron survival (Lefebvre et al, 1997). As well as spinal cord a-MN dysfunction and degeneration, correlates with the extent of SMN loss (Lefebvre et al, 1997). Understanding why SMN loss impairs function should offer insight into SMA and may reveal therapeutic targets. SMN function, has not been linked definitively to MN degeneration or synaptic transmission defects caused by SMN loss
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