Genetic ablation of Dicer in adult forebrain neurons results in abnormal tau hyperphosphorylation and neurodegeneration

The type III RNase Dicer is responsible for the maturation and function of microRNA (miRNA) molecules in the cell. It is now well documented that Dicer and the fine-tuning of the miRNA gene network are important for neuronal integrity. However, the underlying mechanisms involved in neuronal death, particularly in the adult brain, remain poorly defined. Here, we show that absence of Dicer in the adult forebrain is accompanied by a mixed neurodegenerative phenotype. While neuronal loss is observed in the hippocampus, cellular shrinkage is predominant in the cortex. Interestingly, neuronal degeneration coincides with the hyperphosphorylation of endogenous tau at several epitopes previously associated with neurofibrillary pathology. Transcriptome analysis of enzymes involved in tau phosphorylation identified ERK1 as one of the candidate kinases responsible for this event in vivo. We further demonstrate that miRNAs belonging to the miR-15 family are potent regulators of ERK1 expression in mouse neuronal cells and co-expressed with ERK1/2 in vivo. Last, we show that miR-15a is specifically downregulated in Alzheimer's disease brain. In sum, these results support the hypothesis that changes in the miRNA network may contribute to a neurodegenerative phenotype by affecting tau phosphorylation. Dicer KO vs. controlIII型核糖核酸酶Dicer负责细胞内微小RNA（miRNA）分子的成熟与功能发挥。现已广泛证实，Dicer及miRNA基因网络的精细调控对神经元完整性至关重要。然而，其参与神经元死亡（尤其在成年大脑中）的潜在机制仍未明确。本研究发现，成年前脑Dicer缺失会引发混合性神经变性表型：海马体可见神经元丢失，而大脑皮层则以细胞皱缩为主要特征。值得注意的是，神经元变性与内源性tau蛋白在多个此前与神经原纤维病理相关的表位发生过度磷酸化同步出现。对tau蛋白磷酸化相关酶的转录组分析显示，细胞外调节蛋白激酶1（ERK1）是体内介导该过程的候选激酶之一。我们进一步证实，属于miR-15家族的miRNA可在小鼠神经元细胞中强效调控ERK1的表达，并在体内与ERK1/2共表达。最后，我们发现miR-15a在阿尔茨海默病患者的脑组织中特异性下调。综上，本研究结果支持如下假说：miRNA网络的改变可通过影响tau蛋白磷酸化，进而促成神经变性表型的形成。实验分组为Dicer基因敲除（Dicer KO）组与对照组。