Gangliosides are essential in the protection of inflammation and neurodegeneration via maintenance of lipid rafts: elucidation by a series of ganglioside-deficient mutant mice
Gangliosides are essential in the protection of inflammation and neurodegeneration via maintenance of lipid rafts: elucidation by a series of ganglioside-deficient mutant mice
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DOI：
10.1111/j.1471-4159.2010.07067.x
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发表时间：
2011-03-01
影响因子：
4.7
通讯作者：
Furukawa, Koichi
中科院分区：
文献类型：
--
作者：
Ohmi, Yuhsuke;Tajima, Orie;Furukawa, Koichi
神经节苷脂被认为参与神经组织的维护和修复。最近，我们报道了神经节苷脂在补体系统调节中的新作用。在本研究中，我们比较了各种神经节苷脂合酶突变小鼠（即GM2/GD2合酶敲除（KO）、GD3合酶KO、这两种酶的双KO（DKO））和野生型小鼠的补体激活、炎症反应和富含糖脂的微结构域（GEM）/筏的破坏。补体相关基因的上调、C1q 的沉积、星形胶质细胞的增殖和小胶质细胞的浸润也表现出类似的逐渐严重程度，具体取决于神经节苷脂成分的缺陷。在IL-1β和肿瘤坏死因子α等炎症细胞因子的表达中，只有DKO表现出明确的上调。对来自蔗糖密度梯度超速离心的级分进行免疫印迹显示，脂筏标记物如 Caveolin-1 和 flotillin-1 倾向于从脂筏级分中分散，其强度为 DKO > GM2/GD2 合酶 KO > GD3 合酶 KO > 野生型。衰变加速因子和神经细胞粘附分子倾向于从筏部分消失。 GM2/GD2 合酶 KO 和 DKO 中的 GEM/raft 中的磷脂和胆固醇也趋于减少，尽管总量几乎相同。这些结果表明，GEM/筏的破坏是由神经节苷脂缺乏引起的，其强度取决于其组合物的缺陷程度。
Gangliosides are considered to be involved in the maintenance and repair of nervous tissues. Recently, novel roles of gangliosides in the regulation of complement system were reported by us. In this study, we compared complement activation, inflammatory reaction and disruption of glycolipid-enriched microdomain (GEM)/rafts among various mutant mice of ganglioside synthases, i.e. GM2/GD2 synthase knockout (KO), GD3 synthase KO, double KO (DKO) of these two enzymes and wild type. Up-regulation of complement-related genes, deposits of C1q, proliferation of astrocytes and infiltration of microglia also showed similar gradual severity depending on the defects in ganglioside compositions. In the expression of inflammatory cytokines such as IL-1 beta and tumor necrosis factor alpha, only DKO showed definite up-regulation. Immunoblotting of fractions from sucrose density gradient ultracentrifugation revealed that lipid raft markers such as caveolin-1 and flotillin-1 tended to disperse from the raft fractions with intensities of DKO > GM2/GD2 synthase KO > GD3 synthase KO > wild type. Decay-accelerating factor and neural cell adhesion molecule tended to disappear from the raft fraction. Phospholipids and cholesterol also tended to decrease in GEM/rafts in GM2/GD2 synthase KO and DKO, although total amounts were almost equivalent. These results indicate that destruction of GEM/rafts is caused by ganglioside deficiency with gradual intensity depending on the degree of defects of their compositions.