Lecommandeur Emmanuelle, Cachón-González Maria Begoña, Boddie Susannah, McNally Ben D, Nicholls Andrew W, Cox Timothy M, Griffin Julian L
Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge CB2 1GA, UK.
Department of Medicine, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
Metabolites. 2020 Dec 30;11(1):18. doi: 10.3390/metabo11010018.
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 H Nuclear Magnetic Resonance spectroscopy to profile intact lipids and aqueous metabolites, respectively. We examined spinal cord and cerebrum from healthy and 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 -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.
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β-己糖胺酶（HEX）A和B缺乏。SD的特征是神经节苷脂和相关糖脂的积累，主要在中枢神经系统，并进行性神经变性。导致神经变性的潜在细胞机制以及炎症在SD中的作用仍不明确。本研究的目的是测量随时间变化的整体代谢变化，这可能揭示疾病的新分子途径。我们分别使用液相色谱-质谱和氢核磁共振波谱对完整脂质和水性代谢物进行分析。我们在1、2、3和4个月龄时检查了健康小鼠和SD小鼠模型（一种SD小鼠模型）的脊髓和大脑。我们报告了髓鞘典型脂质、半乳糖神经酰胺和缩醛磷脂酰乙醇胺的浓度降低，这表明髓鞘脂质合成减少是疾病病理发展中的早期事件。如N-乙酰天门冬氨酸和氨基酸神经递质浓度降低所示，神经元密度的降低是渐进性的。最后，肌醇含量增加表明的小胶质细胞活化与疾病的晚期症状阶段密切相关。
