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首页> 外文期刊>Aging cell. >p38 MAPK-mediated loss of nuclear RNase III enzyme Drosha underlies amyloid beta-induced neuronal stress in Alzheimer's disease
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p38 MAPK-mediated loss of nuclear RNase III enzyme Drosha underlies amyloid beta-induced neuronal stress in Alzheimer's disease

机译：P38 MAPK介导的核RNase III酶Drosha损失淀粉样蛋白β诱导的阿尔茨海默病神经元应激

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MicroRNAs (miRNAs) are small noncoding RNAs ubiquitously expressed in the brain and regulate gene expression at the post-transcriptional level. The nuclear RNase III enzyme Drosha initiates the maturation process of miRNAs in the nucleus. Strong evidence suggests that dysregulation of miRNAs is involved in many neurological disorders including Alzheimer's disease (AD). Dysfunction of miRNA biogenesis components may be involved in the processes of those diseases. However, the role of Drosha in AD remains unknown. By using immunohistochemistry, biochemistry, and subcellular fractionation methods, we show here that the level of Drosha protein was significantly lower in the postmortem brain of human AD patients as well as in the transgenic rat model of AD. Interestingly, Drosha level was specifically reduced in neurons of the cortex and hippocampus but not in the cerebellum in the AD brain samples. In primary cortical neurons, amyloid-beta (Aβ) oligomers caused a p38?MAPK-dependent phosphorylation of Drosha, leading to its redistribution from the nucleus to the cytoplasm and a decrease in its level. This loss of Drosha function preceded Aβ-induced neuronal death. Importantly, inhibition of p38?MAPK activity or overexpression of Drosha protected neurons from Aβ oligomers-induced apoptosis. Taken together, these results establish a role for p38?MAPK-Drosha pathway in modulating neuronal viability under Aβ oligomers stress condition and implicate loss of Drosha as a key molecular change in the pathogenesis of AD.
机译：MicroRNAs（miRNA）是在脑中脑脑垂直表达的小非编码RNA，并调节转录后水平的基因表达。核RNase III酶DROSHA在细胞核中启动MIRNA的成熟过程。有力的证据表明miRNA的失调涉及许多神经系统疾病，包括阿尔茨海默病（AD）。 miRNA生物生成组分的功能障碍可参与这些疾病的过程中。然而，Drosha在广告中的作用仍然是未知的。通过使用免疫组织化学，生物化学和亚细胞分馏方法，我们在此显示Drosha蛋白的水平在人类广告患者的后期脑中显着降低，以及AD的转基因大鼠模型。有趣的是，Dosha水平在皮质和海马的神经元中明确降低，但不在广告脑样品中的小脑中。在初级皮质神经元中，淀粉样蛋白β（Aβ）低聚物引起P38？依赖于DROSHA的MAPK依赖性磷酸化，导致其从细胞核中的重新分布到细胞质，并降低其水平。这种DROSHA功能的丧失在β-诱导的神经元死亡中。重要的是，抑制P38的MAPK活性或DROSHA保护神经元的抑制来自Aβ低聚物诱导的细胞凋亡。总之，这些结果在调节Aβ低聚物应激条件下调节神经元活力的P38？MAPK-DROSHA途径的作用，并将DROSHA的损失作为AD发病机制的关键分子变化。

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