Transcriptional profiling of differentially vulnerable motor neurons at pre-symptomatic stage in the Smn mouse model of spinal muscular atrophy

Introduction: The term motor neuron disease encompasses a spectrum of disorders in which motor neurons are the lost. Importantly, while some motor neurons are lost early in disease and others remain intact at disease end-stage. This creates a valuable experimental paradigm to investigate the factors that regulate motor neuron vulnerability. Spinal muscular atrophy is a childhood motor neuron disease caused by mutations or deletions in the SMN1 gene. Here, we have performed transcriptional analysis on differentially vulnerable motor neurons from an intermediate mouse model of Spinal muscular atrophy at a presymptomatic time point. Results: We have characterised two differentially vulnerable populations, differing in the level neuromuscular junction loss. Transcriptional analysis on motor neuron cell bodies revealed that reduced Smn levels correlate with a reduction of transcripts associated with the ribosome, rRNA binding, ubiquitination and oxidative phosphorylation. Furthermore, P53 pathway activation precedes neuromuscular junction loss, suggesting that denervation may be a consequence, rather than a cause of motor neuron death in Spinal muscular atrophy. Finally, increased vulnerability correlates with a decrease in the positive regulation of DNA repair. Conclusions: This study identifies pathways related to the function of Smn and associated with differential motor unit vulnerability, thus presenting a number of exciting targets for future therapeutic development. Introduction Motor neuron diseases (MNDs) are a heterogeneous group of neurodegenerative disorders that are caused by a diverse array of factors, including both genetic and sporadic. The clinical severity can also vary widely, but MNDs are frequently very severe, causing fatality within months to years of diagnosis. Despite a range of causes and severities, motor neuron diseases are united by the common vulnerability of motor neurons. The reason why these cells are selectively vulnerable to the genetic or environmental insult is unknown. Importantly, however, not all motor neurons are equally affected [26]. There are some pools of motor neuron in which there are high levels of pathology throughout the motor unit, and high levels of motor neuron loss [6, 22, 27, 16]. In other pools in the same individual, there will be minimal evidence of motor unit pathology, even at late stages of disease. The reasons for this selective vulnerability are currently unknown, however this phenomenon creates an exciting and valuable opportunity to investigate the factors governing motor neuron vulnerability and pathology. By comparing different motor neuron groups we can investigate the molecular mechanisms underlying the disease, the molecular mechanisms underlying motor neuron pathology and the mechanisms that regulate motor neuron vulnerability. Spinal muscular atrophy (SMA) is a childhood motor neuron disease caused by mutations and deletions within the survival motor neuron 1 gene (SMN1). There is a second partially functional copy of the SMN gene, termed SMN2. Due to a point mutation, SMN2 predominantly produces a form of SMN that lacks exon 7, which is * Correspondence: [email protected] Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8 L6, Canada Centre for Integrative Physiology, University of Edinburgh, Edinburgh EH8 9XD, UK Full list of author information is available at the end of the article © 2015 Murray et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Murray et al. Acta Neuropathologica Communications (2015) 3:55 DOI 10.1186/s40478-015-0231-1