Glia-specific activation of all pathways of the unfolded protein response in vanishing white matter disease
Glia-specific activation of all pathways of the unfolded protein response in vanishing white matter disease
复制标题
DOI：
10.1097/01.jnen.0000228201.27539.50
复制
发表时间：
2006-07-01
影响因子：
3.2
通讯作者：
van der Knaap, Marjo S.
中科院分区：
文献类型：
--
作者：
van Kollenburg, Barbara;van Dijk, Jantine;van der Knaap, Marjo S.
伴有白质消失的白质脑病 (VWM) 是一种儿童期白质疾病，具有染色体隐性遗传模式。临床病程呈慢性进行性，伴有发热感染后神经功能快速恶化的发作。该疾病是由编码真核起始因子 2B (eIF2B) 亚基的基因突变引起的，eIF2B 是蛋白质合成所必需的蛋白质复合物。在 VWM 中，eIF2B 基因的突变被认为会损害细胞在正常和应激条件下调节蛋白质合成的能力。有人认为 VWM 的病理生理学涉及未折叠蛋白反应 (UPR) 的不当激活。 UPR 是一种由内质网中未折叠或错误折叠蛋白质超载激活的保护机制。已经在 VWM 患者的脑组织中描述了 UPR 的一种通路（其中涉及 eIF2B）的激活。在本研究中，我们使用实时定量聚合酶链反应和免疫组织化学证明了 VWM 脑组织中所有 3 个 UPR 途径的激活。我们发现激活仅发生在白质中，主要是少突胶质细胞和星形胶质细胞。这些细胞的选择性参与表明不适当的 UPR 激活可能在 VWM 的病理生理学中发挥关键作用。
Leukoencephalopathy with vanishing white matter (VWM) is a childhood white matter disorder with an amosomal-recessive mode of inheritance. The clinical course is chronic progressive with episodes of rapid neurologic deterioration after febrile infections. The disease is caused by mutations in the genes encoding the subunits of eukaryotic initiation factor 2B (eIF2B), a protein complex that is essential for protein synthesis. In VWM, mutations in the eIF2B genes are thought to impair the ability of cells to regulate protein synthesis under normal and stress conditions. It has been suggested that the pathophysiology of VWM involves inappropriate activation of the unfolded protein response (UPR). The UPR is a protective mechanism activated by an overload of unfolded or malfolded proteins in the endoplasmic reticulum. Activation of one pathway of the UPR, in which eIF2B is involved, has already been described in brain tissue of patients with VWM. In the present study, we demonstrate activation of all 3 UPR pathways in VWM brain tissue using real-time quantitative polymerase chain reaction and immunohistochemistry. We show that activation occurs exclusively in the white matter, predominantly in oligodendrocytes and astrocytes. The selective involvement of these cells suggests that inappropriate UPR activation may play a key role in the pathophysiology of VWM.