Murine model of Alexander disease: Analysis of GFAP aggregate formation and its pathological significance
Murine model of Alexander disease: Analysis of GFAP aggregate formation and its pathological significance
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DOI：
10.1002/glia.20486
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发表时间：
2007-04-15
期刊：
影响因子：
6.2
通讯作者：
Ikenaka, Kazuhiro
中科院分区：
文献类型：
--
作者：
Tanaka, Kenji F.;Takebayashi, Hirohide;Ikenaka, Kazuhiro
亚历山大病是由神经胶质纤维酸性蛋白（GFAP）基因编码突变引起的。病理标志是星形胶质细胞内形成称为罗森塔尔纤维（RFs）的细胞质包涵体，其主要由GFAP和几种热休克蛋白组成。突变体GFAP的存在似乎与RF的形成有关；然而，小鼠大脑中野生型人GFAP的过量产生也会导致RF的形成。在这里，我们研究了导致rf样聚集体形成的体内条件。我们使用转基因小鼠（小鼠GFAP启动子-人GFAP cDNA与R239H突变），GFAP转基因的剂量可以在同一基因座内操作。我们发现突变体GFAP本身的存在不足以形成聚集体。相反，GFAP含量也需要比野生型增加30%。GFAP聚集上调内源性GFAP和巢蛋白基因表达，免疫染色显示中间纤维结构破碎。然而，星形胶质细胞的整体形态，包括它们的精细过程，没有受到影响。在该转基因动物模型中，小鼠未表现出带有R239H突变的亚历山大病的大脑畸形、脑白质营养不良或癫痫发作特征。然而，它们在kainate攻击后的死亡率急剧增加，而缺乏聚集物的转基因小鼠的死亡率与野生型小鼠相似。这些结果表明，含有突变GFAP的GFAP聚集体的存在并不足以诱导亚历山大病的主要表型，即使它在小鼠中引起一些异常。(c) 2007 Wiley-Liss, Inc。
Alexander disease is caused by a coding mutation in the glial fibrillary acidic protein (GFAP) gene. The pathological hallmark is the formation of cytoplasmic inclusions within astrocytes known as Rosenthal fibers (RFs), which primarily consist of GFAP and several heat shock proteins. The presence of mutant GFAP would appear to be involved in RF formation; however, overproduction of wild type human GFAP in mouse brain also results in RF formation. Here, we investigated the in vivo conditions leading to formation of RF-like aggregates. We used transgenic mice (mouse GFAP promoter-human GFAP cDNA with R239H mutation) in which the dosage of the GFAP transgene could be manipulated within the same genetic locus. We found that the presence of mutant GFAP per se was insufficient for aggregate formation. Instead, a 30% increase in GFAP content over that in wild type was also required. GFAP aggregates upregulated endogenous GFAP and nestin gene expression, and intermediate filament structure revealed by immunostaining was fragmented under these conditions. However, overall morphology of astrocytes, including their fine processes, was unaffected. In this transgenic animal model, mice did not show megalencephaly, leukodystrophy, or seizure characteristic of Alexander disease with R239H mutation. Nevertheless, their mortality after kainate challenge was dramatically increased, whereas transgenic mice lacking aggregates exhibited mortality similar to that of wild type mice. These results indicate that the presence of GFAP aggregates containing mutant GFAP is not sufficient to induce a major phenotype of Alexander disease, even though it causes some abnormalities in the mouse. (c) 2007 Wiley-Liss, Inc.