Hsa-miR-34b is a plasma-stable microRNA that is elevated in pre-manifest Huntington's disease
Hsa-miR-34b is a plasma-stable microRNA that is elevated in pre-manifest Huntington's disease
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DOI：
10.1093/hmg/ddr111
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发表时间：
2011-06-01
影响因子：
3.5
通讯作者：
Bjorkqvist, Maria
中科院分区：
文献类型：
--
作者：
Gaughwin, Philip Michael;Ciesla, Maciej;Bjorkqvist, Maria
亨廷顿病(HD)是一种毁灭性的神经退行性疾病，缺乏有效的治疗方法。正常亨廷顿蛋白(HTT)和突变亨廷顿蛋白(MHTT)在多种组织中表达，并能改变microRNAs(MiRs)的转录。重要的是，miRs以生物稳定的形式存在于人的外周血浆中，最近被证明是其他疾病的有用生物标志物。因此，我们试图确定HD的潜在miR生物标志物，这些标志物存在于神经元和非神经元组织中，并具有功能后果。在一个高表达mHTT-Exon-1的细胞系中，使用miR微阵列分析来鉴定候选的miRs。然后，我们检查了它们在对照和HD血浆中的存在和生物稳定性。我们发现miR-34b在mHTT-Exon-1作用下显著升高，并且它的阻断在体外改变了mHTT-Exon-1的毒性。我们还表明，miR-34b可以从小输入体积的血浆中检测到，并且对冻融诱导的RNA降解不敏感。有趣的是，在症状出现之前，HD基因携带者的血浆中miR-34b显著升高。这是首次有研究表明血浆miRs可作为HD的生物标志物。
Huntington's disease (HD) is a devastating, neurodegenerative condition, which lacks effective treatment. Normal Huntingtin (HTT) and mutant Huntingtin (mHTT) are expressed in multiple tissues and can alter transcription of microRNAs (miRs). Importantly, miRs are present in a bio-stable form in human peripheral blood plasma and have recently been shown to be useful biomarkers in other diseases. We therefore sought to identify potential miR biomarkers of HD that are present in, and have functional consequences for, neuronal and non-neuronal tissues. In a cell line over-expressing mHTT-Exon-1, miR microarray analysis was used to identify candidate miRs. We then examined their presence and bio-stability in control and HD plasma. We found that miR-34b is significantly elevated in response to mHTT-Exon-1, and its blockade alters the toxicity of mHTT-Exon-1 in vitro. We also show that miR-34b is detectable in plasma from small input volumes and is insensitive to freeze-thaw-induced RNA degradation. Interestingly, miR-34b is significantly elevated in plasma from HD gene carriers prior to symptom onset. This is the first study suggesting that plasma miRs might be used as biomarkers for HD.