Centre for Neuroscience and Trauma, Blizard Institute of Cell and Molecular Science, Queen Mary University of London, UK.
BMC Genomics. 2010 Nov 15;11:633. doi: 10.1186/1471-2164-11-633.
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.
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.
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.
创伤会损害神经功能，并成为发展不可逆转和致命的神经退行性疾病（如肌萎缩侧索硬化症）的风险因素。在这项研究中，我们研究了超氧化物歧化酶 1 (SOD1) 基因突变如何改变对脊髓轻微机械压缩的急性反应。在损伤后 7 天的时间内，我们对表达 G93A-SOD1 基因突变的前症状大鼠和野生型（WT）同窝仔鼠损伤脊髓的基因表达谱进行了比较本体分析。
WT 大鼠观察到的稳定的损伤后功能恢复伴随着损伤中心的几个促生长信号的早期激活，以及中间神经丝和参与离子电流调节的基因的下调。在 G93A-SOD1 转基因动物中观察到的功能恢复不良伴随着较少的促生存信号诱导、炎症标志物的早期激活、参与细胞色素 C 释放的几个促凋亡基因的激活以及重神经丝亚单位和参与膜兴奋性的基因的持续上调。与 WT 同窝仔鼠相比，这些分子变化伴随着 G93A-SOD1 大鼠在压迫损伤后脊髓运动神经元的明显萎缩。
在温和机械创伤的实验模型中，不会造成严重的组织损伤，G93A-SOD1 基因突变改变了前症状大鼠脊髓组织中促凋亡和促生存分子信号之间的平衡，导致与肌萎缩侧索硬化症自然发展相关的分子途径过早激活。
