Transcriptional Profiling in the Lumbar Spinal Cord of a Mouse Model of Amyotrophic Lateral Sclerosis: A Role for Wild-Type Superoxide Dismutase 1 in Sporadic Disease?
Transcriptional Profiling in the Lumbar Spinal Cord of a Mouse Model of Amyotrophic Lateral Sclerosis: A Role for Wild-Type Superoxide Dismutase 1 in Sporadic Disease?
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DOI：
10.1007/s12031-010-9332-2
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发表时间：
2010-07-01
影响因子：
3.1
通讯作者：
Leon, Alberta
中科院分区：
文献类型：
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作者：
D'Arrigo, Antonello;Colavito, Davide;Leon, Alberta
携带铜锌超氧化物歧化酶突变的小鼠在人肌萎缩侧索硬化症中重现脊髓运动神经元变性和疾病进展。我们通过比较突变型G93A-SOD1、野生型SOD1转基因和非转基因小鼠的腰椎脊髓、额顶叶皮层和海马的转录谱，研究了疾病进展与基因表达改变的关系。在G93A小鼠的症状前期和疾病晚期，分别在55天和110日龄时评估基因表达。虽然在皮质和海马区没有检测到明显的变化，但在症状期在腰椎脊髓中检测到一些与突变相关的变化，这与神经元窘迫的情况相一致。此外，在这两个年龄，我们发现了一些与转基因相关的变化，即在两个转基因组中都发生了独立于G93A突变的变化，野生型SOD1-和G93A-SOD1过表达小鼠在110日龄时表现出全球转录相似性。两个转基因组之间的一些共同变化涉及与氧化应激、炎症、脊髓小脑变性和其他神经退行性疾病有关的基因。野生型和突变型人类SOD1过表达小鼠共享潜在与细胞窘迫相关的基因表达改变，这一发现提高了SOD1表达突变（在家族性ALS中）或失调（在散发性ALS中）是该疾病常见致病底物的可能性。
Mice bearing mutations of copper-zinc-superoxide dismutase recapitulate spinal cord motor neuron degeneration and disease progression occurring in human amyotrophic lateral sclerosis. We have investigated the relationship between disease progression and altered gene expression by comparing the transcriptional profiles in lumbar spinal cord, fronto-parietal cortex and hippocampus of mutant G93A-SOD1, wild-type SOD1 transgenic and non-transgenic mice. Gene expression was evaluated at 55 and 110 days of age, representing pre-symptomatic and advanced disease stages of G93A mice, respectively. Whereas no significant variations were detectable in cortical and hippocampal areas, several mutation-related changes were detected in the lumbar spinal cord at the symptomatic stage, consistent with a condition of neuronal distress. Also, at both ages, we found a number of transgene-related changes, i.e. variations occurring in both transgenic groups independently of the G93A mutation, with wild-type SOD1- and G93A-SOD1-overexpressing mice displaying global transcriptional similarity at 110 days of age. Some of the changes in common between the two transgenic groups involve genes implicated in oxidative stress, inflammation, spinocerebellar degeneration and other neurodegenerative disorders. The finding that gene expressional alterations potentially associated to cellular distress are shared by wild-type and mutant human SOD1-overexpressing mice raises the possibility that mutated (in familial ALS) or otherwise dysregulated (in sporadic ALS) SOD1 expression is a common pathogenetic substrate of the disease.