真核细胞翻译启动因子2B与白质消融性白质脑病  

Eukaryotic translation initiation factor 2B and leukoencephalopathy with vanishing white matter

作　　者：潘艳霞[1,2] 吴晔[1] 牛争平[2] 姜玉武[1] 

机构地区：[1]北京大学第一医院儿科,北京100034 [2]山西医科大学第一临床医学院儿科

出　　处：《北京大学学报（医学版）》2009年第5期608-610,共3页Journal of Peking University:Health Sciences

基　　金：国家自然科学基金(30772355, 30872793);北京市自然科学基金(7082093)资助~~

摘　　要：Leukoencephalopathy with vanishing white matter(VWM) is one of the most prevalent inherited white matter disorders in childhood,and it′s the only known hereditary human disease due to the direct defects in protein synthesis process,with the gene defects in EIF2B1-5,encoding the five subunits of eukaryotic translation initiation factor(eIF2B α,β,γ,δ and ε) respectively.eIF2B is essential for the protein translation initiation process,and its action is realized via eukaryotic translation initiation factor2(eIF2).Phosphorylation of eIF2α and eIF2Bε is an important way to regulate eIF2B function,and thus play a key role in control of the protein translation level under physiological condition.Mutant eIF2B results in functional defects and decrease of the overall protein translation in cells,but in increase the translation of proteins with multiple upstream open reading frames,such as activating transcription factor 4(AFT4),which leads to the susceptibility to un-folded protein response under stress,and the following apoptosis.The exact pathogenic mechanisms of VWM are far from well understood.It′s suggested that level of AFT4 in cells with eIF2B mutations is higher than in wild type cells under physiological condition,which makes the mutant cells more susceptible to endoplasmic reticulum(ER) stress and unfolded protein response(UPR).Under stress,the defect eIF2B leads to a vicious cycle of UPR activation,which may underlie the neurological aggravation in VWM patients after minor stress,a specific cli-nical feature of VWM.Elucidating the pathogenesis of VWM will be helpful to further understand the protein translation process in eukaryotic cells,and provide a clue for possible therapeutic targets and treatment strategies in the future.Abstract:SUMM ARY Leukoencephalopathy with vanishing white matter(VWM) is one of the most prevalent in-herited white matter d isorders in childhood,and i′ts the only known hered itary human d isease due to the d irect defects in protein synthesis process,with the gene defectSUMMARY Leukoencephalopathy with vanishing white matter （VWM） is one of the most prevalent inherited white matter disorders in childhood, and it＇s the only known hereditary human disease due to the direct defects in protein synthesis process, with the gene defects in EIF2B1 -5, encoding the five subunits of eukaryotic translation initiation factor （eIF2B α, β, γ, δ and ε） respectively, eIF2B is essential for the protein translation initiation process, and its action is realized via eukaryotic translation initiation factor2 （eIF2）. Phosphorylation of eIF2α and eIF2Bε is an important way to regulate eIF2B function, and thus play a key role in control of the protein translation level under physiological condition. Mutant eIF2B results in functional defects and decrease of the overall protein translation in cells, but in increase the translation of proteins with multiple upstream open reading frames, such as activating transcription factor 4 （AFF4）, which leads to the susceptibility to un-folded protein response under stress, and the following apoptosis. The exact pathogenic mechanisms of VWM are far from well understood. It＇s suggested that level of AFT4 in cells with eIF2B mutations is higher than in wild type cells under physiological condition, which makes the mutant cells more susceptible to endoplasmic reticulum （ER） stress and unfolded protein response （UPR）. Under stress, the defect elF2B leads to a vicious cycle of UPR activation, which may underlie the neurological aggravation in VWM patients after minor stress, a specific clinical feature of VWM. Elucidating the pathogenesis of VWM will be helpful to further understand the protein translation process in eukaryotic cells, and provide a clue for possible therapeutic targets and treatment strategies in the future.

关 键 词：白质消融性白质脑病 真核细胞起始因子 磷酰化 激活转录因子4 

分 类 号：R742[医药卫生—神经病学与精神病学]