Impaired Levels of Gangliosides in the Corpus Callosum of Huntington Disease Animal Models
Impaired Levels of Gangliosides in the Corpus Callosum of Huntington Disease Animal Models
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DOI：
10.3389/fnins.2016.00457
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发表时间：
2016-10-06
影响因子：
4.3
通讯作者：
Maglione, Vittorio
中科院分区：
文献类型：
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作者：
Di Pardo, Alba;Amico, Enrico;Maglione, Vittorio
亨廷顿病（HD）是一种遗传性神经退行性疾病，其特征在于可影响神经元和非神经元细胞群体的广泛类型的细胞和分子功能障碍。在所有的分子机制背后的复杂发病机制的疾病，鞘脂的改变已被确定为最重要的决定因素之一，在过去的几年里。在本研究中，除了进一步证实HD转基因小鼠纹状体和皮质组织中神经节苷脂GM 1、GD 1a和GT 1b（最丰富的脑鞘糖脂）代谢紊乱的证据外，我们还旨在检验以下假设：在胼胝体白色物质中也可能发现这些脂质的异常水平，一个富含神经节苷脂的大脑区域被描述为在疾病早期功能障碍。GM 1、GD 1a和GT 1b含量的半定量分析表明，神经节苷脂代谢是两种不同HD动物模型（YAC 128和R6/2小鼠）的共同特征，重要的是，证明了从疾病早期开始，两种模型的胼胝体白色物质中这些神经节苷脂的水平显著降低。除了证实HD中神经节苷脂代谢异常的证据外，在这里，我们首次发现神经节苷脂功能障碍是HD模型中的早期事件，它可能代表影响疾病发病机制的关键分子变化。
Huntington Disease (HD) is a genetic neurodegenerative disorder characterized by broad types of cellular and molecular dysfunctions that may affect both neuronal and non-neuronal cell populations. Among all the molecular mechanisms underlying the complex pathogenesis of the disease, alteration of sphingolipids has been identified as one of the most important determinants in the last years. In the present study, besides the purpose of further confirming the evidence of perturbed metabolism of gangliosides GM1, GD1a, and GT1b the most abundant cerebral glycosphingolipids, in the striatal and cortical tissues of HD transgenic mice, we aimed to test the hypothesis that abnormal levels of these lipids may be found also in the corpus callosum white matter, a ganglioside-enriched brain region described being dysfunctional early in the disease. Semi-quantitative analysis of GM1, GD1a, and GT1b content indicated that ganglioside metabolism is a common feature in two different HD animal models (YAC128 and R6/2 mice) and importantly, demonstrated that levels of these gangliosides were significantly reduced in the corpus callosum white matter of both models starting from the early stages of the disease. Besides corroborating the evidence of aberrant ganglioside metabolism in HD, here, we found out for the first time, that ganglioside dysfunction is an early event in HD models and it may potentially represent a critical molecular change influencing the pathogenesis of the disease.