Altered Expression of the m6A Methyltransferase METTL3 in Alzheimer's Disease
Altered Expression of the m6A Methyltransferase METTL3 in Alzheimer's Disease
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DOI：
10.1523/eneuro.0125-20.2020
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发表时间：
2020-09-01
期刊：
影响因子：
3.4
通讯作者：
Widagdo, Jocelyn
中科院分区：
文献类型：
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作者：
Huang, He;Camats-Perna, Judith;Widagdo, Jocelyn
阿尔茨海默病（AD）中的认知障碍与脑中RNA和蛋白质表达谱的失调有关。最近的研究强调了RNA转录后调控（epitranscriptomics）在高级脑功能中的重要性。具体来说，N6-甲基腺苷（m6 A），控制RNA的稳定性，剪接，翻译和运输，在学习和记忆中发挥重要作用。这就提出了m6 A信号传导是否在AD中受到干扰的问题。为了解决这个问题，我们使用公共RNA-seq数据集研究了已知m6 A调控基因的表达谱，并确定了在人类AD大脑中显著失调的基因子集。其中，编码m6 A甲基转移酶的基因，胃L3，和m6 A甲基转移酶复合物（MACOM）的成员，RBM 15 B，在海马中分别下调和上调。这些发现在蛋白质水平上使用一组独立的死后人脑样本进行了验证。出乎意料的是，我们观察到不溶性级分中甲基转移酶样3（胃L3）而非RBM 15 B的积累，这与死后人AD样品中不溶性Tau蛋白的水平正相关。因此，AD脑海马中胃L3的异常表达和分布可能代表了与疾病发病机制相关的改变的基因表达模式的表观转录组学机制。
Cognitive impairment in Alzheimer's disease (AD) is associated with dysregulation of the RNA and protein expression profiles in the brain. Recent studies have highlighted the importance of RNA post-transcriptional regulation (epitranscriptomics) in higher order brain functions. Specifically, N6-methyladenosine (m6A), which controls RNA stability, splicing, translation and trafficking, plays an important role in learning and memory. This raises the question of whether m6A signaling is perturbed in AD. To address this, we investigated the expression profile of known m6A-regulatory genes using a public RNA-seq dataset and identified a subset of genes which were significantly dysregulated in the human AD brain. Among these, genes encoding the m6A methyltransferase, METTL3, and a member of the m6A methyltransferase complex (MACOM), RBM15B, were downregulated and upregulated in the hippocampus, respectively. These findings were validated at the protein level using an independent cohort of postmortem human brain samples. Unexpectedly, we observed an accumulation of methyltransferase-like 3 (METTL3), but not RBM15B, in the insoluble fractions, which positively correlated with the levels of insoluble Tau protein in the postmortem human AD samples. Aberrant expression and distribution of METTL3 in the hippocampus of the AD brain may therefore represent an epitranscriptomic mechanism underlying the altered gene expression patterns associated with disease pathogenesis.