title: The human G93A-SOD1 mutation in a pre-symptomatic rat model of amyotrophic lateral sclerosis increases the vulnerability to a mild spinal cord compression.
abstract: BACKGROUND
  Traumatic injuries can undermine neurological functions and act as risk factors for the development of irreversible and fatal neurodegenerative disorders like amyotrophic lateral sclerosis (ALS). In this study, we have investigated how a mutation of the superoxide dismutase 1 (SOD1) gene, linked to the development of ALS, modifies the acute response to a gentle mechanical compression of the spinal cord. In a 7-day post-injury time period, we have performed a comparative ontological analysis of the gene expression profiles of injured spinal cords obtained from pre-symptomatic rats over-expressing the G93A-SOD1 gene mutation and from wild type (WT) littermates.
  
  
  RESULTS
  The steady post-injury functional recovery observed in WT rats was accompanied by the early activation at the epicenter of injury of several growth-promoting signals and by the down-regulation of intermediate neurofilaments and of genes involved in the regulation of ion currents at the 7 day post-injury time point. The poor functional recovery observed in G93A-SOD1 transgenic animals was accompanied by the induction of fewer pro-survival signals, by an early activation of inflammatory markers, of several pro-apoptotic genes involved in cytochrome-C release and by the persistent up-regulation of the heavy neurofilament subunits and of genes involved in membrane excitability. These molecular changes occurred along with a pronounced atrophy of spinal cord motor neurones in the G93A-SOD1 rats compared to WT littermates after compression injury.
  
  
  CONCLUSIONS
  In an experimental paradigm of mild mechanical trauma which causes no major tissue damage, the G93A-SOD1 gene mutation alters the balance between pro-apoptotic and pro-survival molecular signals in the spinal cord tissue from the pre-symptomatic rat, leading to a premature activation of molecular pathways implicated in the natural development of ALS.
authors.affiliation: Centre for Neuroscience and Trauma, Blizard Institute of Cell and Molecular Science, Queen Mary University of London, UK.
authors.forename: Natasa
authors.initials: N
authors.lastname: Jokic
authors.forename: Ping K
authors.initials: PK
authors.lastname: Yip
authors.forename: Adina
authors.initials: A
authors.lastname: Michael-Titus
authors.forename: John V
authors.initials: JV
authors.lastname: Priestley
authors.forename: Andrea
authors.initials: A
authors.lastname: Malaspina
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006801:Humans; D007796:Laminectomy; D008124:Locomotion; D009046:Motor Neurons / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D016900:Neurofilament Proteins / Q000235:genetics / Q000378:metabolism; D009929:Organ Size; D051381:Rats; D020127:Recovery of Function; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013117:Spinal Cord Compression / Q000201:enzymology / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D013119:Spinal Cord Injuries / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D013482:Superoxide Dismutase / Q000235:genetics*; D000072105:Superoxide Dismutase-1; D016708:Synaptophysin / Q000235:genetics / Q000378:metabolism; D013997:Time Factors
chemical_list: D016900:Neurofilament Proteins; C000606290:SOD1 protein, human; D016708:Synaptophysin; C051774:neurofilament protein H; C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1