Encephalopathy Caused by Ablation of Very Long Acyl Chain Ceramide Synthesis May Be Largely Due to Reduced Galactosylceramide Levels
Encephalopathy Caused by Ablation of Very Long Acyl Chain Ceramide Synthesis May Be Largely Due to Reduced Galactosylceramide Levels
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DOI：
10.1074/jbc.m111.261206
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发表时间：
2011-08-26
影响因子：
4.8
通讯作者：
Futerman, Anthony H.
中科院分区：
文献类型：
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作者：
Ben-David, Oshrit;Pewzner-Jung, Yael;Futerman, Anthony H.
鞘脂（SL）作为信号分子和作为神经元细胞和髓鞘中的结构组分起作用。我们现在描述了缺乏极长酰基（C22-C24）链SL的小鼠大脑中的生化、组织学和行为异常。由于神经酰胺合酶2的消除，该小鼠合成C22-C24-SL的能力有缺陷，其半乳糖神经酰胺（GalCer）（髓鞘的主要组分）的水平降低，特别是非羟基-C22-C24-GalCer和2-羟基-C22-C24-GalCer的水平降低。值得注意的脑损伤的发展具有与C22-C24-GalCer在髓磷脂稳定性中的重要作用一致的时间过程。观察到髓鞘变性和脱离，以及源自皮质下区域的异常运动行为。其他异常包括特定脑区的双侧和对称空泡化和神经胶质增生，这在一定程度上对应于神经酰胺合酶2表达的模式，星形胶质增生比小胶质细胞活化明显得多。出乎意料的是，在星形胶质细胞的溶酶体中检测到未鉴定的储存物质，这让人联想到溶酶体储存障碍中发生的积累。总之，我们的数据表明，含有非常长的酰基链的SL在大脑中起着关键作用，特别是GalCer，其水平降低，导致定义的大脑区域中出现独特的形态异常。
Sphingolipids (SLs) act as signaling molecules and as structural components in both neuronal cells and myelin. We now characterize the biochemical, histological, and behavioral abnormalities in the brain of a mouse lacking very long acyl (C22-C24) chain SLs. This mouse, which is defective in the ability to synthesize C22-C24-SLs due to ablation of ceramide synthase 2, has reduced levels of galactosylceramide (GalCer), a major component of myelin, and in particular reduced levels of non-hydroxy-C22-C24-GalCer and 2-hydroxy-C22-C24-GalCer. Noteworthy brain lesions develop with a time course consistent with a vital role for C22-C24-GalCer in myelin stability. Myelin degeneration and detachment was observed as was abnormal motor behavior originating from a subcortical region. Additional abnormalities included bilateral and symmetrical vacuolization and gliosis in specific brain areas, which corresponded to some extent to the pattern of ceramide synthase 2 expression, with astrogliosis considerably more pronounced than microglial activation. Unexpectedly, unidentified storage materials were detected in lysosomes of astrocytes, reminiscent of the accumulation that occurs in lysosomal storage disorders. Together, our data demonstrate a key role in the brain for SLs containing very long acyl chains and in particular GalCer with a reduction in their levels leading to distinctive morphological abnormalities in defined brain regions.