Altered microRNA expression profile in Amyotrophic Lateral Sclerosis: a role in the regulation of NFL mRNA levels.
Altered microRNA expression profile in Amyotrophic Lateral Sclerosis: a role in the regulation of NFL mRNA levels.
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DOI：
10.1186/1756-6606-6-26
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发表时间：
2013-05-24
期刊：
影响因子：
3.6
通讯作者：
Strong MJ
中科院分区：
文献类型：
--
作者：
Campos-Melo D;Droppelmann CA;He Z;Volkening K;Strong MJ
肌萎缩侧索硬化症（ALS）是一种进行性、成人发病、致死性的运动神经元退行性疾病。有新的证据表明，RNA代谢的改变可能是ALS发病机制的关键。microRNA（miRNAs）是一种小的非编码RNA，是mRNA稳定性的关键决定因素。考虑到miRNA越来越多地被认为在各种神经退行性疾病中具有作用，我们决定表征散发性ALS（sALS）和对照组中脊髓（SC）组织中的miRNA表达谱。此外，我们进行了功能分析，以确定一组失调的miRNA，可能是负责选择性抑制低分子量神经丝（NFL）mRNA在ALS中观察到的。使用TaqMan阵列，我们分析了664个miRNA，发现与对照组相比，大量miRNA在sALS腹侧腰SC中差异表达。我们观察到大多数失调的miRNA在sALS SC组织中下调。免疫途径分析（IPA）表明，失调的miRNA与神经系统功能和细胞死亡有关。我们使用两种预测算法开发了一组在人类NFL mRNA 3′UTR内具有识别元件的miRNAs，然后对这些miRNAs进行了功能分析。我们的研究结果表明，在sALS中失调的三种miRNA（miR-146 a *、miR-524- 5 p和miR-582- 3 p）能够与NFL mRNA 3′UTR相互作用，其方式与ALS中脊髓运动神经元中观察到的稳态mRNA水平抑制一致。在sALS的SC中，miRNA表达谱发生了广泛的改变。其中，一组失调的miRNA直接调节NFL mRNA 3′UTR，表明在ALS脊髓运动神经元神经丝聚集体形成中选择性抑制NFL mRNA的作用。
Amyotrophic Lateral Sclerosis (ALS) is a progressive, adult onset, fatal neurodegenerative disease of motor neurons. There is emerging evidence that alterations in RNA metabolism may be critical in the pathogenesis of ALS. MicroRNAs (miRNAs) are small non-coding RNAs that are key determinants of mRNA stability. Considering that miRNAs are increasingly being recognized as having a role in a variety of neurodegenerative diseases, we decided to characterize the miRNA expression profile in spinal cord (SC) tissue in sporadic ALS (sALS) and controls. Furthermore, we performed functional analysis to identify a group of dysregulated miRNAs that could be responsible for the selective suppression of low molecular weight neurofilament (NFL) mRNA observed in ALS. Using TaqMan arrays we analyzed 664 miRNAs and found that a large number of miRNAs are differentially expressed in ventral lumbar SC in sALS compared to controls. We observed that the majority of dysregulated miRNAs are down-regulated in sALS SC tissues. Ingenuity Pathway Analysis (IPA) showed that dysregulated miRNAs are linked with nervous system function and cell death. We used two prediction algorithms to develop a panel of miRNAs that have recognition elements within the human NFL mRNA 3′UTR, and then we performed functional analysis for these miRNAs. Our results demonstrate that three miRNAs that are dysregulated in sALS (miR-146a*, miR-524-5p and miR-582-3p) are capable of interacting with NFL mRNA 3′UTR in a manner that is consistent with the suppressed steady state mRNA levels observed in spinal motor neurons in ALS. The miRNA expression profile is broadly altered in the SC in sALS. Amongst these is a group of dysregulated miRNAs directly regulate the NFL mRNA 3′UTR, suggesting a role in the selective suppression of NFL mRNA in the ALS spinal motor neuron neurofilamentous aggregate formation.
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影响因子：
64.8
作者：
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通讯作者：
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作者：
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影响因子：
56.9
作者：
Kwiatkowski, T. J., Jr.;Bosco, D. A.;Brown, R. H., Jr.
通讯作者：
Brown, R. H., Jr.
影响因子：
4.8
作者：
Ge, WW;Wen, WY;Strong, MJ
通讯作者：
Strong, MJ