title: Transcriptional profiling of differentially vulnerable motor neurons at pre-symptomatic stage in the Smn (2b/-) mouse model of spinal muscular atrophy.
abstract: BACKGROUND
  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.
authors.affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8 L6, Canada. Lyndsay.Murray@ed.ac.uk.|Centre for Integrative Physiology, University of Edinburgh, Edinburgh, EH8 9XD, UK. Lyndsay.Murray@ed.ac.uk.|Euan McDonald Centre for Motor Neuron Disease Research, University of Edinburgh, Edinburgh, EH8 9XD, UK. Lyndsay.Murray@ed.ac.uk.|College of Medicine & Veterinary Medicine, University of Edinburgh, Old Medical School, Teviot Place, Edinburgh, EH8 9XD, UK. Lyndsay.Murray@ed.ac.uk.
authors.forename: Lyndsay M
authors.initials: LM
authors.lastname: Murray
authors.affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8 L6, Canada.
authors.forename: Ariane
authors.initials: A
authors.lastname: Beauvais
authors.affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8 L6, Canada.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Gibeault
authors.affiliation: Centre for Integrative Physiology, University of Edinburgh, Edinburgh, EH8 9XD, UK.|Euan McDonald Centre for Motor Neuron Disease Research, University of Edinburgh, Edinburgh, EH8 9XD, UK.
authors.forename: Natalie L
authors.initials: NL
authors.lastname: Courtney
authors.affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8 L6, Canada.|Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, K1H 8 M5, Canada.|Department of Medicine, University of Ottawa, Ottawa, ON, K1H 8 M5, Canada.|University of Ottawa Center for Neuromuscular Disease, Ottawa, ON, K1H 8 M5, Canada.
authors.forename: Rashmi
authors.initials: R
authors.lastname: Kothary
mesh_terms: D000818:Animals; D058070:Asymptomatic Diseases; D001572:Benzofurans; D002038:Bungarotoxins / Q000378:metabolism; D016923:Cell Death / Q000235:genetics; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000235:genetics*; D007382:Intermediate Filaments / Q000378:metabolism; D061346:Laser Capture Microdissection; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009134:Muscular Atrophy, Spinal / Q000235:genetics* / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009469:Neuromuscular Junction / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D011804:Quinolines; D012269:Ribosomal Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics*; D013997:Time Factors
chemical_list: C576715:(3aS,4S,9bS)-N-(2-(8-cyano-1-formyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo(3,2-c)quinolin-4-yl)-2-methylpropyl)-4,6-difluorobenzofuran-2-carboxyamide; D001572:Benzofurans; D002038:Bungarotoxins; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D011804:Quinolines; D012269:Ribosomal Proteins; C526472:Smn1 protein, mouse; D055533:Survival of Motor Neuron 1 Protein; C489614:Sv2a protein, mouse