Alzheimer's and Parkinson's Disease Laboratory, Brain and Mind Research Institute, University of Sydney, 100 Mallett Street, Camperdown, 2050, Camperdown, Sydney, NSW, Australia.
J Mol Neurosci. 2012 Feb;46(2):324-35. doi: 10.1007/s12031-011-9587-2. Epub 2011 Jul 1.
MicroRNAs (miRNAs) are small non-coding RNA regulators of protein synthesis that are essential for normal brain development and function. Their profiles are significantly altered in neurodegenerative diseases such as Alzheimer's disease (AD) that is characterized by amyloid-β (Aβ) and tau deposition in brain. How deregulated miRNAs contribute to AD is not understood, as their dysfunction could be both a cause and a consequence of disease. To address this question we had previously profiled miRNAs in models of AD. This identified miR-9 and -181c as being down-regulated by Aβ in hippocampal cultures. Interestingly, there was a remarkable overlap with those miRNAs that are deregulated in Aβ-depositing APP23 transgenic mice and in human AD tissue. While the Aβ precursor protein APP itself is a target of miRNA regulation, the challenge resides in identifying further targets. Here, we expand the repertoire of miRNA target genes by identifying the 3' untranslated regions (3' UTRs) of TGFBI, TRIM2, SIRT1 and BTBD3 as being repressed by miR-9 and -181c, either alone or in combination. Taken together, our study identifies putative target genes of miRNAs miR-9 and 181c, which may function in brain homeostasis and disease pathogenesis.
微小 RNA（miRNA）是蛋白质合成的小非编码 RNA 调节剂，对于正常的大脑发育和功能至关重要。它们的谱在神经退行性疾病中发生显著改变，例如以脑内淀粉样蛋白-β（Aβ）和 tau 沉积为特征的阿尔茨海默病（AD）。尚未了解失调的 miRNA 如何导致 AD，因为其功能障碍可能既是疾病的原因又是后果。为了解决这个问题，我们之前曾在 AD 模型中对 miRNA 进行了分析。这确定了 miR-9 和 -181c 被 Aβ 在海马培养物中下调。有趣的是，这与在 Aβ 沉积 APP23 转基因小鼠和人类 AD 组织中失调的 miRNA 存在显著重叠。虽然 APP 前体蛋白 APP 本身是 miRNA 调节的靶标，但挑战在于识别其他靶标。在这里，我们通过鉴定 TGFBI、TRIM2、SIRT1 和 BTBD3 的 3' 非翻译区（3'UTR）被 miR-9 和 -181c 单独或组合抑制，扩展了 miRNA 靶基因的组合。总之，我们的研究确定了 miRNA miR-9 和 181c 的潜在靶基因，它们可能在大脑内稳态和疾病发病机制中发挥作用。
