Edinburgh Research Explorer

Motyl AAL, et al. (2020). Pre-symptomatic developmental phenotypes in Spinal Muscular Atrophy


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PublisherEdinburgh DataShare
Date made available3 Mar 2020


Spinal muscular atrophy (SMA) is a leading genetic cause of infant death, characterised primarily by a loss of lower motor neurons. SMA is caused by mutations in the survival motor neuron 1 (SMN1) gene. New SMN-restoring therapies for SMA have emerged in recent years; however, data from both pre-clinical and clinical studies demonstrate that there is a limited therapeutic time-window for them to be effective. Moreover, it is now clear that peripheral organs and tissues can also be affected by the disease. To better understand the earliest changes occurring during SMA, with implications for defining the optimum time and location of therapy delivery, we undertook a detailed anatomical, histological and molecular analysis of pre-symptomatic, prenatal changes occurring in a mouse model of SMA. We generated 3D-renderings of whole embryos at embryonic day (E)14.5 using micro-computed tomography (µCT). These analyses showed that E14.5 SMA embryos are significantly smaller than littermate controls, indicative of a general developmental delay. Cardiac ventricles were smaller in SMA heart, whilst liver and brain volumes remained unaffected. Morphometric and histological analyses showed no overt structural defects indicative of degenerative pathology in any of the organs examined. We then performed a comparative proteomics' screen of spinal cord, brain, liver, skeletal muscle and heart in SMA and control mice using Tandem Mass Tagging mass spectrometry. This revealed significant molecular perturbations in all organs examined, with the liver showing the greatest magnitude of change. Notably, we found a lack of overlap in affected proteins and molecular pathways between organs, highlighting tissue-specific prenatal molecular phenotypes in SMA. Together, our data demonstrate that considerable changes are already present across numerous tissues and organs at an early, pre-symptomatic stage in SMA mice, suggesting that there is a significant developmental component to SMA pathogenesis.

Data Citation

Motyl, Anna Abigail Lydia; Gillingwater, Thomas; Wishart, Thomas. (2020). Motyl AAL, et al. (2020). Pre-symptomatic developmental phenotypes in Spinal Muscular Atrophy, [dataset]. University of Edinburgh. College of Medicine and Veterinary Medicine. https://doi.org/10.7488/ds/2776.

ID: 142707588