Molecular mechanism of the formation of the cerebral white matter lesion.

最近，编码真核细胞翻译起始因子2B(EIF2B)亚单位的基因突变被确定为白质消失性脑病(VWM)的原因。EIF2B在蛋白质合成的翻译起始调控中发挥重要作用。我们在成人发病的VWM中发现了一种新的EIF2B突变。我们假设Binswanger病的EIF异常可能导致Binswanger病的脑白质损害，共16例，包括5例年龄匹配的对照组，5例Binswanger病患者，6例其他疾病。采用脑白质切片，ABC法进行免疫组织化学染色。Binswanger组GFAP阳性细胞数与正常对照组比较差异无统计学意义。另一方面，我们发现在Binswanger病的脑白质病变中，磷酸化eIF2α阳性星形胶质细胞的数量增加。EIF2α是eIF2B的竞争性抑制因子。因此，我们推测eIF2mRNA的磷酸化、eIF2B的功能障碍、α翻译减少和星形胶质细胞功能障碍可能是Binswanger病白质损害的原因。我们进一步检测了CREB-2、GADD、磷酸化GCN-2、磷酸化MAPK在尸检脑和慢性脑缺血动物模型中的表达。Binswanger病脑白质损害形成的分子机制尚需进一步研究。

Recently, mutations in the genes encoding the subunits of the eukaryotic translation initiation factor 2B (eIF2B) have been identified as the cause of leukoencephalopathy with vanishing white matter (VWM). EIF2B plays an important role in the regulation of translation initiation of protein synthesis. We identified a novel EIF2B mutation in adult-onset VWM. We hypothesized the abnormality of eIF in Binswanger disease may cause the white matter lesions of Binswanger disesase.We used a total number of 16 cases constituting of 5 age matched control, 5 patients with Binswanger disease, 6 other disease. We used the section from the cerebral white matter.Immunohistochemistry by using ABC method were performed. The number of GFAP positive cell showed no significant difference between Binswanger group and normal control. On the other hand, We identified the increased number of the phosphorylated eIF2α positive astrocytes in the cerebral white matter lesion in Binswanger disease. EIF2α is a competitive inhibitor of eIF2B. Therefore, we hypothesized that phosphorylation of eIF2α, dysfunction of eIF2B, reduced mRNA translation and dysfunction of astrocytes may be the cause of white matter damage of Binswanger disease. We further examined the expression of CREB-2, GADD, phosphorylated GCN-2, phosphorylated MAPK in the autopsied brains and the animal model of chronic ischemia. We did not get the significant difference.We need a further research to identify the molecular mechanism of the formation of the cerebral white matter lesion of Binswanger disease.