Survival Motor Neuron Protein in Motor Neurons Determines Synaptic Integrity in Spinal Muscular Atrophy

Abstract

The inherited motor neuron disease spinal muscular atrophy (SMA) is caused by deficient expression of survival motor neuron (SMN) protein and results in severe muscle weakness. In SMA mice, synaptic dysfunction of both neuromuscular junctions (NMJs) and central sensorimotor synapses precedes motor neuron cell death. To address whether this synaptic dysfunction is due to SMN deficiency in motor neurons, muscle, or both, we generated three lines of conditional SMA mice with tissue-specific increases in SMN expression. All three lines of mice showed increased survival, weights, and improved motor behavior. While increased SMN expression in motor neurons prevented synaptic dysfunction at the NMJ and restored motor neuron somal synapses, increased SMN expression in muscle did not affect synaptic function although it did improve myofiber size. Together these data indicate that both peripheral and central synaptic integrity are dependent on motor neurons in SMA, but SMN may have variable roles in the maintenance of these different synapses. At the NMJ, it functions at the presynaptic terminal in a cell-autonomous fashion, but may be necessary for retrograde trophic signaling to presynaptic inputs onto motor neurons. Importantly, SMN also appears to function in muscle growth and/or maintenance independent of motor neurons. Our data suggest that SMN plays distinct roles in muscle, NMJs, and motor neuron somal synapses and that restored function of SMN at all three sites will be necessary for full recovery of muscle power.

Motor neuron cell-nonautonomous rescue of spinal muscular atrophy phenotypes in mild and severe transgenic mouse models

“…However, the mouse prion promoter used in that study is also active in many nonneuronal cell types and peripheral tissues (Brown et al 1990), which may have contributed to phenotypic rescue. Indeed, several recent studies using various mouse models showed that restoring SMN expression only in motor neurons or pan-neuronally resulted in a limited survival increase (Gogliotti et al 2012;Lee et al 2012;Martinez et al 2012). In accordance with these findings, we recently demonstrated an essential role of SMN expression in peripheral tissues for long-term rescue of severe SMA mice .…”

“…On the other hand, in several studies, including our own, selective depletion of SMN in motor neurons induces NMJ defects, and restoration of SMN rescues them, indicating a cell-autonomous mechanism (Park et al 2010;Gogliotti et al 2012;Lee et al 2012;Martinez et al 2012;Sahashi et al 2012Sahashi et al , 2013. This apparent discrepancy may be due to the extremely low SMN levels in motor neurons in these studies.…”

“…Sensory motor synaptic defects in the spinal cord have also been observed (Ling et al 2010;Park et al 2010;Mentis et al 2011). Three recent studies demonstrated that both peripheral and central synaptic defects are autonomously caused by insufficient levels of SMN in motor neurons (Gogliotti et al 2012;Lee et al 2012;Martinez et al 2012). However, increasing SMN levels in motor neurons, although sufficient to restore both NMJ and sensory motor synaptic integrity, only partially ameliorates the phenotype of SMA mice, including a limited increase in survival (Gogliotti et al 2012;Lee et al 2012;Martinez et al 2012).…”

“…Three recent studies demonstrated that both peripheral and central synaptic defects are autonomously caused by insufficient levels of SMN in motor neurons (Gogliotti et al 2012;Lee et al 2012;Martinez et al 2012). However, increasing SMN levels in motor neurons, although sufficient to restore both NMJ and sensory motor synaptic integrity, only partially ameliorates the phenotype of SMA mice, including a limited increase in survival (Gogliotti et al 2012;Lee et al 2012;Martinez et al 2012). These data suggest that defects in tissues other than motor neurons contribute substantially to the rapid mortality of mice with severe SMA.…”

“…However, although there is a reduction in muscle fiber number and size (due to compromised muscle growth, lack of myofiber maturation, and premature differentiation of satellite cells), the importance of muscle SMN levels in SMA pathology is controversial (Braun et al 1995;Gavrilina et al 2008;Lee et al 2011;Hayhurst et al 2012). Martinez et al (2012) recently demonstrated that increased SMN in muscle-including myoblasts and satellite cells, two cell types critical for muscle growth and maintenanceslightly extends the survival of SMA mice, supporting the conclusion that the deficiency of SMN in muscles also contributes to the mortality of SMA mice.…”