Transcriptome Profiling Following Neuronal and Glial Expression of ALS-Linked SOD1 in Drosophila.
Transcriptome Profiling Following Neuronal and Glial Expression of ALS-Linked SOD1 in Drosophila.
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DOI：
10.1534/g3.113.005850
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发表时间：
2013-04-09
期刊：
影响因子：
--
通讯作者：
Zhang B
中科院分区：
文献类型：
--
作者：
Kumimoto EL;Fore TR;Zhang B
肌萎缩侧索硬化症（ALS）通常是一种迟发性神经退行性疾病。Cu/Zn超氧化物歧化酶1（SOD 1）基因突变约占家族性ALS的20%和所有ALS病例的2%。虽然已经提出了许多假说来解释突变SOD 1毒性，但该疾病的分子机制仍不清楚。SOD 1相关的ALS被认为以非细胞自主的方式起作用，使得运动神经元对于发病至关重要，并且神经胶质有助于疾病的进展。最近，它已被证明在果蝇中，在一个子集的神经元细胞中的人SOD 1的表达引起突触传递缺陷，修改运动功能，并改变敏感性的化合物，诱导氧化应激。在这里，我们使用的Gal 4-UAS（上游激活序列）系统，以进一步表征果蝇表达野生型果蝇SOD 1（dSOD 1）和突变的人SOD 1G 85 R（G85 R）等位基因的运动神经元和神经胶质。发现dSOD 1和G85 R的细胞特异性表达影响寿命，影响对过氧化氢的敏感性，并改变脂质过氧化水平。为了更好地理解G85 R在运动神经元和神经胶质中表达的遗传后果，我们对选择性地在运动神经元或神经胶质中表达G85 R的年轻果蝇（5天龄）和老年果蝇（45天龄）以及同时在运动神经元和神经胶质中表达G85 R进行了微阵列分析。微阵列实验的结果确定了进一步研究的候选基因，可能有助于阐明运动神经元和神经胶质细胞在ALS中的单独和联合作用。
Amyotrophic lateral sclerosis (ALS) generally is a late-onset neurodegenerative disease. Mutations in the Cu/Zn superoxide dismutase 1 (SOD1) gene account for approximately 20% of familial ALS and 2% of all ALS cases. Although a number of hypotheses have been proposed to explain mutant SOD1 toxicity, the molecular mechanisms of the disease remain unclear. SOD1-linked ALS is thought to function in a non–cell-autonomous manner such that motoneurons are critical for the onset, and glia contribute to progression of the disease. Recently, it has been shown in Drosophila melanogaster that expression of human SOD1 in a subset of neuronal cells causes synaptic transmission defects, modified motor function, and altered sensitivity to compounds that induce oxidative stress. Here we used the Gal4-UAS (Upstream Activation Sequence) system to further characterize flies expressing wild-type Drosophila SOD1 (dSOD1) and the mutant human SOD1G85R (G85R) allele in motoneurons and glia. Cell-specific expression of both dSOD1 and G85R was found to influence lifespan, affect sensitivity to hydrogen peroxide, and alter lipid peroxidation levels. To better understand the genetic consequences of G85R expression in motoneurons and glia, we conducted microarray analysis of both young flies (5 days old) and old flies (45 days old) expressing G85R selectively in motoneurons or glia and concurrently in motoneurons and glia. Results from this microarray experiment identified candidate genes for further investigation and may help elucidate the individual and combined contributions of motoneurons and glia in ALS.
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