Department of Experimental Medical Sciences, Wallenberg Neuroscience Center, Lund University, S-221 84 Lund, Sweden.
Hum Mol Genet. 2011 Jun 1;20(11):2225-37. doi: 10.1093/hmg/ddr111. Epub 2011 Mar 19.
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.
亨廷顿病（HD）是一种破坏性的神经退行性疾病，目前缺乏有效的治疗方法。正常的亨廷顿蛋白（HTT）和突变的亨廷顿蛋白（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类外周血浆中，最近在其他疾病中被证明是有用的生物标志物。因此，我们试图确定存在于神经元和非神经元组织中，并对其具有功能影响的 HD 的潜在 miR 生物标志物。在过表达 mHTT-Exon-1 的细胞系中，使用 miR 微阵列分析来鉴定候选 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 对 mHTT-Exon-1 的反应明显升高，其阻断会改变 mHTT-Exon-1 的体外毒性。我们还表明，miR-34b 可以从小体积的血浆中检测到，并且不受冻融诱导的 RNA 降解的影响。有趣的是，miR-34b 在症状出现前的 HD 基因携带者的血浆中显著升高。这是第一项表明血浆 miRs 可能被用作 HD 生物标志物的研究。
