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Requirement of enhanced Survival Motoneuron protein imposed during neuromuscular junction maturation
Shingo Kariya, … , Shunichi Homma, Umrao R. Monani
Shingo Kariya, … , Shunichi Homma, Umrao R. Monani
Published January 27, 2014
Citation Information: J Clin Invest. 2014;124(2):785-800. https://doi.org/10.1172/JCI72017.
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Research Article Article has an altmetric score of 22

Requirement of enhanced Survival Motoneuron protein imposed during neuromuscular junction maturation

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Abstract

Spinal muscular atrophy is a common motor neuron disease caused by low survival motoneuron (SMN), a key protein in the proper splicing of genes. Restoring the protein is therefore a promising therapeutic strategy. Implementation of this strategy, however, depends on defining the temporal requirements for SMN. Here, we used controlled knockdown of SMN in transgenic mice to determine the precise postnatal stage requirements for this protein. Reducing SMN in neonatal mice resulted in a classic SMA-like phenotype. Unexpectedly, depletion of SMN in adults had relatively little effect. Insensitivity to low SMN emerged abruptly at postnatal day 17, which coincided with establishment of the fully mature neuromuscular junction (NMJ). Mature animals depleted of SMN eventually exhibited evidence of selective neuromuscular pathology that was made worse by traumatic injury. The ability to regenerate the mature NMJ in aged or injured SMN-depleted mice was grossly impaired, a likely consequence of the inability to meet the surge in demand for motoneuronal SMN that was seen in controls. Our results demonstrate that relative maturity of the NMJ determines the temporal requirement for the SMN protein. These observations suggest that the use of potent but potentially deleterious SMN-enhancing agents could be tapered in human patients once the neuromuscular system matures and reintroduced as needed to enhance SMN for remodeling aged or injured NMJs.

Authors

Shingo Kariya, Teresa Obis, Caterina Garone, Turgay Akay, Fusako Sera, Shinichi Iwata, Shunichi Homma, Umrao R. Monani

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Figure 8

A model encapsulating the postnatal requirement for the SMN protein in the murine model.

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A model encapsulating the postnatal requirement for the SMN protein in t...
The requirement for the protein is adequately met by 1 or more SMN1 copies or SMN2 copies that, between them, express equivalent levels of the protein. This requirement is at its greatest during the neonatal period encompassing NMJ refinement and maturation. It eventually falls by approximately P20, a time point defined by the establishment of the fully mature neuromuscular synapse (see photomicrographs), to levels that are satisfied by 2 SMN2 copies. In the approximately 3-day window prior to this time point, mice become relatively resistant to low SMN. Injury of the NMJ during aging or trauma is accompanied by a surge in demand for the protein, specifically in tissues of the neuromuscular system, which is not adequately met by 2 SMN2 copies. The enhanced requirement appears to peak as the NMJ matures and brings about, in SMN-depleted mutants, an inability to fully repair the neuromuscular synapse. Thus, SMN is thought to play 2 related roles at the neuromuscular synapse — its initial maturation and its continued maintenance. Note: figure not drawn to scale.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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