Abstract
The selective vulnerability of motor neurons to paucity of Survival Motor Neuron (SMN) protein is a defining feature of human spinal muscular atrophy (SMA) and indicative of a unique requirement for adequate levels of the protein in these cells. However, the relative contribution of SMN-depleted motor neurons to the disease process is uncertain and it is possible that their characteristic loss and the overall SMA phenotype is a consequence of low protein in multiple cell types including neighboring spinal neurons and non-neuronal tissue. To explore the tissue-specific requirements for SMN and, especially, the salutary effects of restoring normal levels of the protein to neuronal tissue of affected individuals, we have selectively expressed the protein in neurons of mice that model severe SMA. Expressing SMN pan-neuronally in mutant mice mitigated specific aspects of the disease phenotype. Motor performance of the mice improved and the loss of spinal motor neurons that characterizes the disease was arrested. Proprioceptive synapses on the motor neurons were restored and defects of the neuromuscular junctions mitigated. The improvements at the cellular level were reflected in a four-fold increase in survival. Nevertheless, mutants expressing neuronal SMN did not live beyond three weeks of birth, a relatively poor outcome compared to the effects of ubiquitously restoring SMN. This suggests that although neurons and, in particular, spinal motor neurons constitute critical cellular sites of action of the SMN protein, a truly effective treatment of severe SMA will require restoring the protein to multiple cell types including non-neuronal tissue.
Highlights
Spinal muscular atrophy (SMA) is a common, autosomal recessive neuromuscular disease caused by mutations in the Survival of Motor Neurons 1 (SMN1) gene and loss of protein from the gene [1,2,3]
The Smn rescue allele was originally generated to determine the temporal requirements for the Survival Motor Neuron (SMN) protein and includes a hybrid genomic cassette consisting of murine Smn exon 7 in a reverse (39R59) orientation flanked by exons 7 and 8 of the SMN2 gene [28]
Spinal motor neurons are predominantly affected in two other neurodegenerative diseases, amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy with respiratory distress (SMARD1) [40,41,42]
Summary
Spinal muscular atrophy (SMA) is a common, autosomal recessive neuromuscular disease caused by mutations in the Survival of Motor Neurons 1 (SMN1) gene and loss of protein from the gene [1,2,3]. A common characteristic of SMA patients, from the severely affected to the mildly disposed, is evidence of early death or dysfunction of the spinal motor neurons [8,9]. This is true of animal models as well [10,11,12,13], suggesting that motor neurons are sensitive to SMN paucity and the SMA phenotype mostly a consequence of motor neuron loss. In light of reduced proprioceptive synapses on SMA motor neurons, [21,22,23] is a primary or, perhaps, an exacerbating effect of diseased Ia sensory neurons
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