Inhibition of GM3 Synthase Attenuates Neuropathology of Niemann-Pick Disease Type C by Affecting Sphingolipid Metabolism
Inhibition of GM3 Synthase Attenuates Neuropathology of Niemann-Pick Disease Type C by Affecting Sphingolipid Metabolism
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DOI：
10.14348/molcells.2014.2347
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发表时间：
2014-02-28
影响因子：
3.8
通讯作者：
Jin, Hee Kyung
中科院分区：
文献类型：
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作者：
Lee, Hyun;Lee, Jong Kil;Jin, Hee Kyung
在几种溶酶体贮积症中，包括 C 型尼曼-匹克病 (NP-C)，鞘脂，包括鞘糖脂，特别是神经节苷脂，是大脑中主要的储存物质，这增加了这些脂质的积累可能参与 NP-C 神经退行性过程的可能性。然而，这些积累与 NP-C 神经病理学之间的相关性尚未得到充分表征。在这里，我们衍生了 Siat9（编码 GM3 合酶）基因完全和部分缺失的 NP-C 小鼠，以研究神经节苷脂在 NP-C 发病机制中的作用。根据我们的结果，GM3合酶纯合缺失的NP-C小鼠表现出增强的神经病理表型，并且死亡时间明显早于NP-C小鼠。值得注意的是，与完全缺失相比，部分缺失 GM3 合酶基因的 NP-C 小鼠表现出 NP-C 神经病理学改善，包括运动障碍、脱髓鞘以及胆固醇和鞘脂的异常积累。这些发现表明 GM3 合成在 NP-C 表型和 CNS 病理异常进展中的关键作用，表明良好控制的 GM3 合成抑制可用作治疗策略。
In several lysosomal storage disorders, including Niemann-Pick disease Type C (NP-C), sphingolipids, including glycosphingolipids, particularly gangliosides, are the predominant storage materials in the brain, raising the possibility that accumulation of these lipids may be involved in the NP-C neurodegenerative process. However, correlation of these accumulations and NP-C neuropathology has not been fully characterized. Here we derived NP-C mice with complete and partial deletion of the Siat9 (encoding GM3 synthase) gene in order to investigate the role of ganglioside in NP-C pathogenesis. According to our results, NP-C mice with homozygotic deletion of GM3 synthase exhibited an enhanced neuropathological phenotype and died significantly earlier than NP-C mice. Notably, in contrast to complete depletion, NP-C mice with partial deletion of the GM3 synthase gene showed ameliorated NP-C neuropathology, including motor disability, demyelination, and abnormal accumulation of cholesterol and sphingolipids. These findings indicate the crucial role of GM3 synthesis in the NP-C phenotype and progression of CNS pathologic abnormality, suggesting that well-controlled inhibition of GM3 synthesis could be used as a therapeutic strategy.