Transcriptional profile of primary astrocytes expressing ALS-linked mutant SOD1.
Transcriptional profile of primary astrocytes expressing ALS-linked mutant SOD1.
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表达ALS连接突变体SOD1的原代星形胶质细胞的转录谱。
DOI：
10.1002/jnr.21797
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发表时间：
2008-12
影响因子：
4.2
通讯作者：
Barbeito, Luis
中科院分区：
文献类型：
--
作者：
Vargas, Marcelo R.;Pehar, Mariana;Diaz-Amarilla, Pablo J.;Beckman, Joseph S.;Barbeito, Luis
肌萎缩侧索硬化症（ALS）是由运动神经元的进行性变性引起的。在大约20%的家族性ALS患者中发现了Cu/Zn超氧化物歧化酶（SOD 1）的突变。突变SOD 1通过获得性毒性特性导致运动神经元死亡。虽然这种毒性功能获得的分子机制仍然未知，但证据支持非神经元细胞中突变型SOD 1表达在形成运动神经元变性中的作用。我们以前发现，与非转基因细胞相比，表达SOD 1G 93 A的星形胶质细胞诱导共培养的运动神经元凋亡。这促使我们研究对运动神经元存活的影响是否与基因表达谱的变化有关。通过高密度寡核苷酸微阵列，我们发现了参与转录，信号传导，细胞增殖，细胞外基质合成，应激反应以及类固醇和脂质代谢的基因表达的变化。上调最多的基因是核心蛋白聚糖（Dcn），一种小的多功能细胞外蛋白聚糖。下调的基因包括胰岛素样生长因子-1受体（Igf-1 r）和RNA结合蛋白ROD 1。Rod 1在表达SOD 1G 93 A的纯化运动神经元中也被发现下调。在无症状动物的脊髓中发现Dcn、Igf-1 r和Rod 1表达的变化，表明这些变化发生在明显的神经元变性之前，并可能影响疾病过程中星形胶质细胞-运动神经元的相互作用。星形胶质细胞特异性基因表达谱可能有助于识别ALS细胞类型特异性疗法的可能候选者。
Amyotrophic lateral sclerosis (ALS) is caused by the progressive degeneration of motor neurons. Mutations in the Cu/Zn superoxide dismutase (SOD1) are found in about 20% of patients with familial ALS. Mutant SOD1 causes motor neuron death through an acquired toxic property. Although the molecular mechanism underlying this toxic gain-of-function remains unknown, evidence support the role of mutant SOD1 expression in non-neuronal cells in shaping motor neuron degeneration. We have previously found that in contrast to non-transgenic cells, SOD1G93A-expressing astrocytes induced apoptosis of co-cultured motor neurons. This prompted us to investigate whether the effect on motor neuron survival was related to a change in the gene expression profile. Through high-density oligonucleotide microarrays, we found changes in the expression of genes involved in transcription, signaling, cell proliferation, extracellular matrix synthesis, response to stress and steroid and lipid metabolism. The most up-regulated gene was decorin (Dcn), a small multifunctional extracellular proteoglycan. Down-regulated genes included the insulin-like growth factor-1 receptor (Igf-1r) and the RNA binding protein ROD1. Rod1 was also found downregulated in purified motor neurons expressing SOD1G93A. Changes in the expression of Dcn, Igf-1r and Rod1 were found in the spinal cord of asymptomatic animals, suggesting these changes occur before overt neuronal degeneration and potentially influence astrocyte-motor neuron interaction in the course of the disease. The astrocyte-specific gene expression profile might contribute to the identification of possible candidates for cell type-specific therapies in ALS.
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