miR-107 Regulates Granulin/Progranulin with Implications for Traumatic Brain Injury and Neurodegenerative Disease
miR-107 Regulates Granulin/Progranulin with Implications for Traumatic Brain Injury and Neurodegenerative Disease
复制标题
DOI：
10.2353/ajpath.2010.091202
复制
发表时间：
2010-07-01
影响因子：
6
通讯作者：
Nelson, Peter T.
中科院分区：
文献类型：
--
作者：
Wang, Wang-Xia;Wilfred, Bernard R.;Nelson, Peter T.
颗粒蛋白(GRN，或原颗粒蛋白)是一种与伤口修复、炎症和肿瘤有关的蛋白质。GRN还直接与额颞叶痴呆有关，并可能参与阿尔茨海默病的发病机制。然而，对GRN的调控表达知之甚少。高通量实验microRNA分析表明，GRN是人H4神经胶质瘤细胞中miR-107的最强靶点。MiR-107与阿尔茨海默病的发病机制有关，而GRN mRNA开放阅读框架中的序列元件--而不是3‘非翻译区--是由miR-107识别的，并且在脊椎动物中高度保守。为了更好地了解这种相互作用的机制，在miR-107转染后使用了标记了ArgAerte的构建物。在体外和体内的研究表明，miR-107对GRN的调控可能具有重要的功能。在培养细胞中补充葡萄糖导致miR-107水平升高，也会导致GRN表达下降，包括细胞分隔区的改变和GRN蛋白分泌的减少。这一效应在miR-107转染后被消除。我们还测试了一个小鼠模型，其中miR-107被证明是下调的。在深度为10 mm的控制性皮质撞击的脑组织中，存活的海马神经元miR-107随着神经元GRN表达的增加而减少。这些发现表明miR-107参与了GRN的表达调控，并可能与大脑疾病有关。(Am J Pathol2010,177：334-345；DOI：10.2353/ajpath.2010.091202)
Granulin (GRN, or progranulin) is a protein involved in wound repair, inflammation, and neoplasia. GRN has also been directly implicated in frontotemporal dementia and may contribute to Alzheimer's disease pathogenesis. However, GRN regulation expression is poorly understood. A high-throughput experimental microRNA assay showed that GRN is the strongest target for miR-107 in human H4 neuroglioma cells. miR-107 has been implicated in Alzheimer's disease pathogenesis, and sequence elements in the open reading frame-rather than the 3 ' untranslated region-of GRN mRNA are recognized by miR-107 and are highly conserved among vertebrate species. To better understand the mechanism of this interaction, FLAG-tagged Argonaute constructs were used following miR-107 transfection. GRN mRNA interacts preferentially with Argonaute 2. In vitro and in vivo studies indicate that regulation of GRN by miR-107 may be functionally important. Glucose supplementation in cultured cells that leads to increased miR-107 levels also results in decreased GRN expression, including changes in cell compartmentation and decreased secretion of GRN protein. This effect was eliminated following miR-107 transfection. We also tested a mouse model where miR-107 has been shown to be down-regulated. In brain tissue subjacent to 1 0 mm depth controlled cortical impact, surviving hippocampal neurons show decreased miR-107 with augmentation of neuronal GRN expression. These findings indicate that miR-107 contributes to GRN expression regulation with implications for brain disorders. (Am J Pathol 2010, 177:334-345; DOI: 10.2353/ajpath.2010.091202)