A point mutation in translation initiation factor 2B leads to a continuous hyper stress state in oligodendroglial-derived cells.
A point mutation in translation initiation factor 2B leads to a continuous hyper stress state in oligodendroglial-derived cells.
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DOI：
10.1371/journal.pone.0003783
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发表时间：
2008
期刊：
影响因子：
3.7
通讯作者：
Elroy-Stein O
中科院分区：
文献类型：
--
作者：
Kantor L;Pinchasi D;Mintz M;Hathout Y;Vanderver A;Elroy-Stein O
真核生物翻译起始因子2B（eIF 2B）突变导致儿童共济失调伴中枢神经系统髓鞘形成不足（CACH），也称为消失性白色病（VWM）。这种疾病表现为在生理应激时脑髓鞘的损失。在以前的研究中，我们发现从CACH/VWM患者中分离的成纤维细胞对药理学诱导的内质网（ER）应激超敏感。由于受影响个体的脑细胞无法用于研究，我们希望评估eIF 2B突变对少突胶质细胞衍生细胞的影响。大鼠少突胶质细胞衍生的细胞系用于eIF 2B 5的稳定敲低，随后稳定表达突变的eIF 2B 5（R195 H）cDNA。响应于药理学ER-应激剂，表达eIF 2B 5（R195 H）的细胞表现出增强的ER-应激反应，这通过ATF 4、GADD 34、Bip、PDIA 1、PDIA 3、PDIA 4和PDIA 6蛋白的超诱导来证明。此外，即使在不存在药理学应激剂的情况下，eIF 2B 5（R195 H）表达细胞也表现出高基础水平的ATF 4、GADD 34和ER相关Bip、PDIA 1和PDIA 3。这些数据提供了证据表明，表达突变eIF 2B的少突胶质细胞衍生的细胞不断使用其应激反应机制作为适应手段以生存。目前的研究是第一个证明eIF 2B 5突变对少突胶质细胞源性细胞ER稳态的影响。
Mutations in eukaryotic translation initiation factor 2B (eIF2B) cause Childhood Ataxia with CNS Hypomyelination (CACH), also known as Vanishing White Matter disease (VWM). The disease is manifested by loss of brain myelin upon physiological stress. In a previous study, we showed that fibroblasts isolated from CACH/VWM patients are hypersensitive to pharmacologically-induced endoplasmic reticulum (ER) stress. Since brain cells from affected individuals are not available for research, we wished to assess the effect of eIF2B mutation on oligodendroglial-derived cells. A rat oligodendroglial-derived cell line was used for a stable knock-down of eIF2B5 followed by stable expression of mutated eIF2B5(R195H) cDNA. In response to a pharmacological ER-stress agent, eIF2B5(R195H) expressing cells exhibited heightened ER-stress response demonstrated by hyper induction of ATF4, GADD34, Bip, PDIA1, PDIA3, PDIA4 and PDIA6 proteins. Moreover, even in the absence of a pharmacological stress agent, eIF2B5(R195H)-expressing cells exhibited high basal levels of ATF4, GADD34 and ER-associated Bip, PDIA1 and PDIA3. The data provide evidence that oligodendroglial-derived cells expressing a mutated eIF2B constantly use their stress response mechanism as an adaptation mean in order to survive. The current study is the first to demonstrate the effects of eIF2B5 mutation on ER homeostasis in oligodendroglial-derived cells.
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影响因子：
4.8
作者：
Tanaka, S;Uehara, T;Nomura, Y
通讯作者：
Nomura, Y
影响因子：
4.4
作者：
Mintz, Michelle;Vanderver, Adeline;Hathout, Yetrib
通讯作者：
Hathout, Yetrib
影响因子：
11.4
作者：
EIZENBERG, O;FABERELMAN, A;SCHWARTZ, M
通讯作者：
SCHWARTZ, M
DOI：
10.1016/0304-4165(94)90079-5
发表时间：
1994-12-15
影响因子：
3
作者：
KIMBALL, SR;KARINCH, AM;JEFFERSON, LS
通讯作者：
JEFFERSON, LS
影响因子：
30.8
作者：
Senderek, J;Krieger, M;Zerres, K
通讯作者：
Zerres, K