Sandhoff disease (SD) is a lysosomal disease caused by mutations in the gene coding for the β subunit of β-hexosaminidase, leading to deficiency in the enzymes β-hexosaminidase (HEX) A and B. SD is characterised by an accumulation of gangliosides and related glycolipids, mainly in the central nervous system, and progressive neurodegeneration. The underlying cellular mechanisms leading to neurodegeneration and the contribution of inflammation in SD remain undefined. The aim of the present study was to measure global changes in metabolism over time that might reveal novel molecular pathways of disease. We used liquid chromatography-mass spectrometry and ¹H Nuclear Magnetic Resonance spectroscopy to profile intact lipids and aqueous metabolites, respectively. We examined spinal cord and cerebrum from healthy and Hexb^−/− mice, a mouse model of SD, at ages one, two, three and four months. We report decreased concentrations in lipids typical of the myelin sheath, galactosylceramides and plasmalogen-phosphatidylethanolamines, suggesting that reduced synthesis of myelin lipids is an early event in the development of disease pathology. Reduction in neuronal density is progressive, as demonstrated by decreased concentrations of N-acetylaspartate and amino acid neurotransmitters. Finally, microglial activation, indicated by increased amounts of myo-inositol correlates closely with the late symptomatic phases of the disease.

中文翻译：

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通过代谢组学确定，髓磷脂相关脂质的减少先于 Sandhoff 小鼠中枢神经系统的神经元丢失和胶质细胞激活

桑德霍夫病 (SD) 是一种溶酶体疾病，由编码 β-己糖胺酶 β 亚基的基因突变引起，导致酶 β-己糖胺酶 (HEX) A 和 B 缺乏。SD 的特征是神经节苷脂和相关的糖脂，主要存在于中枢神经系统和进行性神经变性中。导致神经变性和炎症在 SD 中的作用的潜在细胞机制仍未明确。本研究的目的是测量代谢随时间的整体变化，这可能揭示疾病的新分子途径。我们使用液相色谱-质谱法和¹ H 核磁共振光谱法分别分析完整的脂质和水性代谢物。我们检查了健康人的脊髓和大脑Hexb ^-/-小鼠，一种 SD 小鼠模型，分别为 1、2、3 和 4 个月大。我们报告了典型的髓鞘脂质、半乳糖苷神经酰胺和缩醛磷脂-磷脂酰乙醇胺的浓度降低，表明髓鞘脂质合成减少是疾病病理学发展的早期事件。神经元密度的降低是渐进的，如N-乙酰天冬氨酸和氨基酸神经递质浓度降低所证明的。最后，小神经胶质细胞的激活（表现为肌醇含量增加）与疾病的晚期症状密切相关。