Division of Molecular Medicine, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3050, Australia.
J Mol Neurosci. 2010 May;41(1):172-82. doi: 10.1007/s12031-009-9317-1. Epub 2009 Dec 2.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition in which motor neurons of the spinal cord and motor cortex degenerate, resulting in progressive paralysis. Transgenic mice expressing human mutant Cu/Zn superoxide dismutase-1 (SOD1) present a pathology that is very similar to that seen in human ALS patients. Using serial analysis of gene expression, we investigated the effects of mutant human SOD1 protein on global gene expression in the spinal cord and lower brain stem of presymptomatic TgSOD1(G93A) transgenic mice. One hundred twenty transcripts were found to be significantly dysregulated in the presence of mutant SOD1 protein, 79 being down-regulated and 41 up-regulated. Quantitative RT-PCR was used to confirm the differential expression of nine of these genes. Immunohistochemistry analysis on spinal cord sections revealed that dysregulation of these mutant SOD1-induced molecular pathways are concomitant to the appearance of discrete signs of neuropathology including neuronal loss, elevated gliosis, and ubiquitin-positive deposits. Altogether, our data showed that early signs of neuropathology in the SOD1 mutant mice are accompanied by altered expression of genes involved in various biological processes including apoptosis, oxidative stress, ATP biosynthesis, myelination, and axonal transport.
肌萎缩性侧索硬化症（ALS）是一种致命的神经退行性疾病，脊髓和大脑皮层的运动神经元退化，导致进行性瘫痪。表达人类突变型 Cu/Zn 超氧化物歧化酶-1（SOD1）的转基因小鼠表现出与人类 ALS 患者非常相似的病理学。我们使用基因表达序列分析研究了突变型人 SOD1 蛋白对预症状 TgSOD1（G93A）转基因小鼠脊髓和下脑干中全局基因表达的影响。在存在突变型 SOD1 蛋白的情况下，发现 120 个转录本明显失调，其中 79 个下调，41 个上调。实时定量 RT-PCR 用于验证其中 9 个基因的差异表达。脊髓切片的免疫组织化学分析表明，这些突变型 SOD1 诱导的分子途径的失调伴随着神经病理学的明显迹象，包括神经元丢失、神经胶质细胞增生和泛素阳性沉积物。总之，我们的数据表明，SOD1 突变型小鼠的早期神经病理学迹象伴随着参与各种生物学过程的基因表达改变，包括细胞凋亡、氧化应激、ATP 生物合成、髓鞘形成和轴突运输。
