Alexander disease causing mutations in the C-terminal domain of GFAP are deleterious both to assembly and network formation with the potential to both activate caspase 3 and decrease cell viability.
Alexander disease causing mutations in the C-terminal domain of GFAP are deleterious both to assembly and network formation with the potential to both activate caspase 3 and decrease cell viability.
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DOI：
10.1016/j.yexcr.2011.06.017
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发表时间：
2011-10-01
影响因子：
3.7
通讯作者：
Perng, Ming-Der
中科院分区：
文献类型：
--
作者：
Chen, Yi-Song;Lim, Suh-Ciuan;Chen, Mei-Hsuan;Quinlan, Roy A.;Perng, Ming-Der
Alexander病是一种原发的星形胶质细胞遗传病，由星形胶质细胞特有的中间丝胶质纤维酸性蛋白(GFAP)的显性突变引起。虽然到目前为止所描述的大多数致病突变都是在保守的α-螺旋杆状结构域中发现的，但也有一些突变在C末端的非α-螺旋尾部结构域中发现。在这里，我们比较了位于GFAP C-末端结构域的五个不同突变(N386I、S393I、S398F、S398Y和D417M14X)在体外和瞬时转染培养细胞中对细丝组装特性的影响。所有的突变都破坏了体外的细丝组装。突变还影响GFAP在瞬时转染的MCF7、SW13和U343 MG细胞中的溶解性和促进细丝聚集。这与p38应激激活蛋白激酶的激活以及与小热休克蛋白的伴侣蛋白αB-晶状体蛋白的相关性增加有关。在所研究的突变体中，D417M14X GFAP对体外和瞬时转染细胞中的细丝组装都产生了最显著的影响。该突变体还引起广泛的细丝聚集，与αB-晶体蛋白和热休克蛋白27的隔离以及蛋白酶体的抑制和p38激酶的激活相一致。与这些变化相关的是caspase3的激活和星形胶质细胞活力的显著下降。我们的结论是，GFAP C末端的一些突变与caspase3的切割和细胞活力的丧失有关，提示这些可能是Alexander病的发病因素。
Alexander disease is a primary genetic disorder of astrocyte caused by dominant mutations in the astrocyte-specific intermediate filament glial fibrillary acidic protein (GFAP). While most of the disease-causing mutations described to date have been found in the conserved α-helical rod domain, some mutations are found in the C-terminal non-α-helical tail domain. Here, we compare five different mutations (N386I, S393I, S398F, S398Y and D417M14X) located in the C-terminal domain of GFAP on filament assembly properties in vitro and in transiently transfected cultured cells. All the mutations disrupted in vitro filament assembly. The mutations also affected the solubility and promoted filament aggregation of GFAP in transiently transfected MCF7, SW13 and U343MG cells. This correlated with the activation of the p38 stress-activated protein kinase and an increased association with the small heat shock protein (SHSP) chaperone, αB-crystallin. Of the mutants studied, D417M14X GFAP caused the most significant effects both upon filament assembly in vitro and in transiently transfected cells. This mutant also caused extensive filament aggregation coinciding with the sequestration of αB-crystallin and HSP27 as well as inhibition of the proteosome and activation of p38 kinase. Associated with these changes were an activation of caspase 3 and a significant decrease in astrocyte viability. We conclude that some mutations in the C-terminus of GFAP correlate with caspase 3 cleavage and the loss of cell viability, suggesting that these could be contributory factors in the development of Alexander disease.
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