Megalencephalic leukoencephalopathy with cysts: the Glialcam-null mouse model.
Megalencephalic leukoencephalopathy with cysts: the Glialcam-null mouse model.
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DOI：
10.1002/acn3.405
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发表时间：
2017-07
影响因子：
5.3
通讯作者：
van der Knaap MS
中科院分区：
文献类型：
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作者：
Bugiani M;Dubey M;Breur M;Postma NL;Dekker MP;Ter Braak T;Boschert U;Abbink TEM;Mansvelder HD;Min R;van Weering JRT;van der Knaap MS
巨脑白质脑病伴囊肿（MLC）是一种遗传性婴儿发病性疾病，其特征为MLC 1功能丧失导致的大头畸形和白色水肿。MLC 1或GLIALCAM中的隐性突变导致该疾病。MLC 1参与星形胶质细胞体积调节; GlialCAM确保MLC 1的正确膜定位。它们在脑离子水稳态中的确切作用仅部分确定。我们对Glialcam-null小鼠进行了表征以进行进一步研究。我们研究了GlialCAM缺失小鼠中GlialCAM缺失的后果，并比较了小鼠和男性中GlialCAM的发育表达。 Glialcam-null小鼠具有早发性巨脑畸形和脑含水量增加。从3周开始，星形胶质细胞异常，肿胀的突起邻接血管。同时，由于髓鞘内水肿，出现进行性白色物质空泡化。Glialcam-null星形胶质细胞显示MLC 1的表达消失，氯离子通道ClC-2的表达减少，水通道水通道蛋白4的表达和再分布增加。其他MLC 1相互作用蛋白和体积调节阴离子通道LRRC 8A的表达没有变化。在小鼠中，GlialCAM表达增加直到3周，然后稳定。在人类中，GlialCAM表达在前3年最高，然后从大约5年开始下降并稳定。 Glialcam-null小鼠复制了人类疾病的早期阶段，具有早发性髓鞘内水肿。最早的变化是星形胶质细胞肿胀，进一步证实星形胶质细胞体积调节缺陷是MLC中的主要细胞缺陷。GlialCAM表达影响MLC 1、ClC-2和水通道蛋白4的表达，表明这些蛋白质之间的异常相互作用是巨脑白质脑病伴囊肿的疾病机制。
Megalencephalic leukoencephalopathy with cysts (MLC) is a genetic infantile‐onset disease characterized by macrocephaly and white matter edema due to loss of MLC1 function. Recessive mutations in either MLC1 or GLIALCAM cause the disease. MLC1 is involved in astrocytic volume regulation; GlialCAM ensures the correct membrane localization of MLC1. Their exact role in brain ion‐water homeostasis is only partly defined. We characterized Glialcam‐null mice for further studies. We investigated the consequences of loss of GlialCAM in Glialcam‐null mice and compared GlialCAM developmental expression in mice and men. Glialcam‐null mice had early‐onset megalencephaly and increased brain water content. From 3 weeks, astrocytes were abnormal with swollen processes abutting blood vessels. Concomitantly, progressive white matter vacuolization developed due to intramyelinic edema. Glialcam‐null astrocytes showed abolished expression of MLC1, reduced expression of the chloride channel ClC‐2 and increased expression and redistribution of the water channel aquaporin4. Expression of other MLC1‐interacting proteins and the volume regulated anion channel LRRC8A was unchanged. In mice, GlialCAM expression increased until 3 weeks and then stabilized. In humans, GlialCAM expression was highest in the first 3 years to then decrease and stabilize from approximately 5 years. Glialcam‐null mice replicate the early stages of the human disease with early‐onset intramyelinic edema. The earliest change is astrocytic swelling, further substantiating that a defect in astrocytic volume regulation is the primary cellular defect in MLC. GlialCAM expression affects expression of MLC1, ClC‐2 and aquaporin4, indicating that abnormal interplay between these proteins is a disease mechanism in megalencephalic leukoencephalopathy with cysts.