Rescuing motor neurons improves symptoms in mouse models of spinal muscular atrophy (SMA), but the animals do not live any longer than untreated controls. Systemic repair, on the other hand, restores normal lifespan, suggesting that other tissues contribute to pathology. But which cells? In the June 20 Journal of Neuroscience, scientists from Johns Hopkins University, Baltimore, Maryland, report that muscle tissue might need rescue in SMA as well. Although it is unlikely that the mouse model used perfectly parallels the human disease, the work has implications for SMA therapies currently under trial.

Spinal muscular atrophy affects peripheral motor neurons in infants and children. The muscle weakness in SMA results from defects in the survival of motor neuron (SMN) gene. Despite its cell-specific name, SMN pervades all cell types at low levels, said senior author Charlotte Sumner. By selectively replacing SMN in specific tissues, the team addressed whether the neuromuscular junction (NMJ) defects observed in SMA mice are due solely to the lack of neuronal SMN, or whether muscle SMN deficiency also contributes. Joint first authors Tara Martinez and Lingling Kong bred SMA mice carrying a Cre-dependent, inducible SMN allele to mice expressing Cre in neurons or in muscle.

Martinez and colleagues found that young SMA mice expressing SMN in motor neurons moved similarly to wild-type mice. They spent the same amount of time upright, traveled the same distance, and reared on their hind legs as often. At 10 days of age, they possessed one-quarter more motor neurons, in the lumbar 1 segment of the spinal cord, than did SMA mice without any Cre. According to electrophysiology experiments, neural SMN restored NMJ function to normal.

Restoring SMN to muscles led to wider muscle fibers and thicker muscles than in SMA controls or SMA mice expressing a good copy of SMN in neurons. However, that muscle bulk did not boost mouse mobility. The muscle-SMN animals had no increase in motor neuron numbers or NMJ transmissions.

These results confirm that motor neurons are the crucial site of SMA pathology, according to Sumner. Unfortunately, “if we put SMN back into motor neurons alone ... there was minimal benefit to the overall survival of the mice,” Sumner said. Neuronal rescue afforded an extra week of life over typical SMA mice—the same as muscle rescue. In comparison, other researchers have shown that adding back SMN systemically extends survival by more than a year (Hua et al., 2011). “That suggests that the disease is more complicated than simply having vulnerable motor neurons,” Sumner concluded. She believes that other cell types contribute to the pathology. Because muscle expression of SMN also helped the animals slightly, she thinks SMN may play a secondary role in muscle, perhaps in myofiber growth.

Christine DiDonato of Children’s Hospital of Chicago Research Center in Illinois obtained similar results restoring SMN in the motor neurons of SMA mice (Gogliotti et al., 2012). The interesting thing, she told Alzforum, was that “the animals … essentially died on their feet.” It was not motor neuron pathology that killed them, but heart failure caused by defects in their autonomic nervous systems, DiDonato suspects (Heier et al., 2010; Bevan et al., 2010; Shababi et al., 2010). This suggests that motor neurons are not the only nerves that rely on SMN to function. Children with SMA also have high rates of heart arrhythmias, DiDonato told ARF.

“I think you have to consider the whole neural circuit,” said Arthur Burghes of Ohio State University in Columbus, who was not involved in either paper. Interneurons, for example, might also suffer from lack of SMN, he suggested. Burghes was skeptical about the importance of muscle. Sumner agreed that muscles are less critical to SMA than are motor neurons, but is developing mice that have SMN restored to both muscle and motor neurons to look for additive or synergistic effects.

Doctors are currently testing a therapy to restore proper SMN transcripts to children with SMA. In this trial, the treatment will be injected intrathecally so it reaches the central nervous system. Sumner is optimistic that SMN in the central nervous system will be beneficial, as long as children get treatment before motor neurons begin to disappear. However, another possible interpretation of her results is that non-nervous tissues such as muscle will need SMN back, too. “Extended survival may unmask other deficits,” as it did in the mice that suffered heart failure, DiDonato speculated. “Further work is required to understand other organ systems that are important in SMA.”—Amber Dance.

Reference:
Martinez TL, Kong L, Wang X, Osborne MA, Crowder ME, Van Meerbeke JP, Xu X, Davis C, Wooley J, Goldhamer DJ, Lutz CM, Rich MM, Sumner CJ. Survival Motor Neuron protein in motor neurons determines synaptic integrity in spinal muscular atrophy. J Neurosci. 2012 Jun 20;32(25):8703-15. Abstract

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References

Paper Citations

  1. . Peripheral SMN restoration is essential for long-term rescue of a severe spinal muscular atrophy mouse model. Nature. 2011 Oct 6;478(7367):123-6. PubMed.
  2. . Motor neuron rescue in spinal muscular atrophy mice demonstrates that sensory-motor defects are a consequence, not a cause, of motor neuron dysfunction. J Neurosci. 2012 Mar 14;32(11):3818-29. PubMed.
  3. . Arrhythmia and cardiac defects are a feature of spinal muscular atrophy model mice. Hum Mol Genet. 2010 Oct 15;19(20):3906-18. PubMed.
  4. . Early heart failure in the SMNDelta7 model of spinal muscular atrophy and correction by postnatal scAAV9-SMN delivery. Hum Mol Genet. 2010 Oct 15;19(20):3895-905. PubMed.
  5. . Cardiac defects contribute to the pathology of spinal muscular atrophy models. Hum Mol Genet. 2010 Oct 15;19(20):4059-71. PubMed.
  6. . Survival Motor Neuron Protein in Motor Neurons Determines Synaptic Integrity in Spinal Muscular Atrophy. J Neurosci. 2012 Jun 20;32(25):8703-8715. PubMed.

External Citations

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Further Reading

Papers

  1. . The survival of motor neuron (SMN) protein interacts with the mRNA-binding protein HuD and regulates localization of poly(A) mRNA in primary motor neuron axons. J Neurosci. 2011 Mar 9;31(10):3914-25. PubMed.
  2. . Survival Motor Neuron Protein in Motor Neurons Determines Synaptic Integrity in Spinal Muscular Atrophy. J Neurosci. 2012 Jun 20;32(25):8703-8715. PubMed.
  3. . Interaction of survival of motor neuron (SMN) and HuD proteins with mRNA cpg15 rescues motor neuron axonal deficits. Proc Natl Acad Sci U S A. 2011 Jun 21;108(25):10337-42. PubMed.
  4. . CNS-targeted gene therapy improves survival and motor function in a mouse model of spinal muscular atrophy. J Clin Invest. 2010 Apr 1;120(4):1253-64. PubMed.

Primary Papers

  1. . Survival Motor Neuron Protein in Motor Neurons Determines Synaptic Integrity in Spinal Muscular Atrophy. J Neurosci. 2012 Jun 20;32(25):8703-8715. PubMed.