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

BackgroundTraumatic 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.ResultsThe 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.ConclusionsIn 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.

The Omega-3 Fatty Acid Eicosapentaenoic Acid Accelerates Disease Progression in a Model of Amyotrophic Lateral Sclerosis

“…To determine the neuronal changes in the spinal cord, immunohistochemistry and quantitative analysis was carried out as previously described [26]. Neurons and more specifically motor neurons were visualized with the immunomarkers NeuN and ChAT, respectively.…”

Can Transcriptomics Cut the Gordian Knot of Amyotrophic Lateral Sclerosis?

“…Recently, Jokic et al . [ 52 ] investigated the gene expression profile of the spinal cord in SOD1(G93A) rats in response to mild compression. Shortly after injury, the expression of genes involved in inflammation and apoptosis was significantly increased while that of genes related to angiogenesis appeared reduced.…”

“…The changes in mRNA levels do not necessarily translate into modifications in protein amounts. Classically, findings from gene profiling studies have been validated by additional sets of experimental approaches, including immunohisto-chemistry [ 29 , 31 - 33 , 35 , 45 , 52 , 54 , 71 ] and Western blot [ 25 , 27 , 31 , 33 , 52 ]. However, combining transcriptomics with proteomics and/or metabolomics should enrich the interpretation of the results.…”

Inflammation is increased with anxiety- and depression-like signs in a rat model of spinal cord injury

“…Following injury, microglia, macrophages, and astrocytes are recruited to the site of trauma. Pro-inflammatory cytokine genes and other inflammation-related genes are up-regulated within hours of injury (Dumont, Okonkwo et al 2001, Yip and Malaspina 2012), and some remain elevated for weeks following the injury (Malaspina, Jokic et al 2008, Jokic, Yip et al 2010). For example, in the hours following injury, the interleukin-6 gene ( IL-6 ), the TNF gene, and the interleukin-1β gene ( IL-1β ) are up-regulated (Hayashi, Ueyama et al 2000, Pan, Ni et al 2002).…”