胶质细胞病——伴皮层下囊肿的巨脑性脑白质病致病机制研究进展

Research Progress of Pathological Mechanism in Megalencephalic Leukoencephalopathy With Subcortical Cysts

伴皮层下囊肿的巨脑性脑白质病(MLC)是MLC1或GlialCAM突变导致的星形胶质细胞功能障碍的中枢神经系统髓鞘变性疾病,以星形胶质细胞肿胀与髓鞘囊泡形成为特征性病理改变。MLC/GlialCAM与ClC-2共定位于星形胶质细胞终足处,既往研究发现MLC1/GlialCAM突变后影响ClC-2通道的电容传导性,导致星形胶质细胞的水离子稳态失衡参与MLC的发病,但在GlialCAM纯合敲除的小鼠中,通过与选择性开放Clc-2通道的转基因小鼠杂交并不能纠正小鼠表型,提示有其他因素共同参与了MLC的发生发展。最近研究表明,突变后的MLC1通过促进Connexin43的内化,减少其在细胞膜处形成缝隙连接,影响细胞间通讯效率,从而导致水肿形成和髓鞘囊泡形成,进一步导致MLC的发生。这些研究提示,少突胶质细胞、星形胶质细胞及缝隙连接蛋白等构成的胶质细胞合胞体的功能异常是MLC致病机制的研究方向。

Megalencephalic leukoencephalopathy(MLC)with subcortical cysts is a degenerative disease of the central nervous system caused by mutations in MLC1 or GlialCAM,characterized with astrocyte swelling and vesicle formation of myelin.MLC/GlialCAM and ClC-2 co-localize at the end feet of astrocytes.Previous studies discovered that MLC1/GlialCAM mutation affects the conductivity of ClC-2 channels,resulting in the imbalance of water and ion homeostasis in astrocytes,while in the GlialCAM homozygous knockout mouse,the phenotype cannot be rescued by crossing with transgenic mice that selectively open ClC-2.Recent study showed that mutated MLC1 promotes the internalization of Connexin43 and reduced the formation of gap junctions at the cell membrane,affected the efficiency of intercellular communication,and interrupted normal glial syncytial function,which led to MLC with astrocyte edema and the vesicle formation of myelin.It indicated that the abnormal function of glial syncytia composed of astrocytes,oligodendrocytes and connexins needs further investigation.