EIF2B5 mutations compromise GFAP+ astrocyte generation in vanishing white matter leukodystrophy
EIF2B5 mutations compromise GFAP+ astrocyte generation in vanishing white matter leukodystrophy
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DOI：
10.1038/nm1195
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发表时间：
2005-03-01
期刊：
影响因子：
82.9
通讯作者：
Pröschel, C
中科院分区：
文献类型：
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作者：
Dietrich, J;Lacagnina, M;Pröschel, C
白色物质消失病（VWM）是一种与翻译起始因子2B（eIF 2B）突变相关的遗传性脑白质营养不良。虽然这种疾病的临床过程已经得到了相对较好的描述，但EIF2B突变对神经细胞的细胞后果尚不清楚。在这里，我们已经建立了从一个人的大脑与VWM携带突变的eIF2B亚基5（EIF2B5编码）的细胞培养。尽管广泛的脱髓鞘明显在这个VWM患者，正常出现的少突胶质细胞很容易在体外产生。相反，在原代培养物中存在很少的GFAP表达（GFAP（+））星形胶质细胞，星形胶质细胞的诱导严重受损，并且产生的很少的星形胶质细胞显示出异常的形态和抗原表型。体内病变也缺乏GFAP（+）星形胶质细胞。靶向EIF2B5的RNAi严重损害了从正常人胶质祖细胞诱导GFAP（+）细胞。这提出了星形胶质细胞功能缺陷可能导致VWM脑白质营养不良中白色物质丢失的可能性。
Vanishing white matter disease (VWM) is a heritable leukodystrophy linked to mutations in translation initiation factor 2B (eIF2B). Although the clinical course of this disease has been relatively well described, the cellular consequences of EIF2B mutations on neural cells are unknown. Here we have established cell cultures from the brain of an individual with VWM carrying mutations in subunit 5 of eIF2B (encoded by EIF2B5). Despite the extensive demyelination apparent in this VWM patient, normal-appearing oligodendrocytes were readily generated in vitro. In contrast, few GFAP-expressing (GFAP(+)) astrocytes were present in primary cultures, induction of astrocytes was severely compromised, and the few astrocytes generated showed abnormal morphologies and antigenic phenotypes. Lesions in vivo also lacked GFAP(+) astrocytes. RNAi targeting of EIF2B5 severely compromised the induction of GFAP(+) cells from normal human glial progenitors. This raises the possibility that a deficiency in astrocyte function may contribute to the loss of white matter in VWM leukodystrophy.