Department of Medical Biochemistry, Academic Medical Center, Amsterdam, The Netherlands.
Blood. 2011 Oct 20;118(16):e118-27. doi: 10.1182/blood-2011-05-352971. Epub 2011 Aug 25.
Gaucher disease, caused by a deficiency of the lysosomal enzyme glucocerebrosidase, leads to prominent glucosylceramide accumulation in lysosomes of tissue macrophages (Gaucher cells). Here we show glucosylsphingosine, the deacylated form of glucosylceramide, to be markedly increased in plasma of symptomatic nonneuronopathic (type 1) Gaucher patients (n = 64, median = 230.7 nM, range 15.6-1035.2 nM; normal (n = 28): median 1.3 nM, range 0.8-2.7 nM). The method developed for mass spectrometric quantification of plasma glucosylsphingosine is sensitive and robust. Plasma glucosylsphingosine levels correlate with established plasma markers of Gaucher cells, chitotriosidase (ρ = 0.66) and CCL18 (ρ = 0.40). Treatment of Gaucher disease patients by supplementing macrophages with mannose-receptor targeted recombinant glucocerebrosidase results in glucosylsphingosine reduction, similar to protein markers of Gaucher cells. Since macrophages prominently accumulate the lysoglycosphingolipid on glucocerebrosidase inactivation, Gaucher cells seem a major source of the elevated plasma glucosylsphingosine. Our findings show that plasma glucosylsphingosine can qualify as a biomarker for type 1 Gaucher disease, but that further investigations are warranted regarding its relationship with clinical manifestations of Gaucher disease.
戈谢病是由于溶酶体酶葡萄糖脑苷脂酶的缺乏引起的，导致组织巨噬细胞（戈谢细胞）溶酶体中葡萄糖鞘氨醇的积累显著增加。在这里，我们发现葡萄糖神经酰胺的去酰化形式，即葡萄糖神经酰胺，在有症状的非神经病变（1 型）戈谢病患者的血浆中明显增加（n = 64，中位数为 230.7 nM，范围为 15.6-1035.2 nM；正常 n = 28：中位数为 1.3 nM，范围为 0.8-2.7 nM）。我们开发的用于定量检测血浆葡萄糖神经酰胺的质谱方法具有很高的灵敏度和稳定性。血浆葡萄糖神经酰胺水平与已建立的戈谢细胞血浆标志物，即壳三糖苷酶（ρ = 0.66）和 CCL18（ρ = 0.40）相关。通过用甘露糖受体靶向的重组葡萄糖脑苷脂酶补充巨噬细胞来治疗戈谢病患者，可导致葡萄糖神经酰胺的减少，这与戈谢细胞的蛋白质标志物相似。由于巨噬细胞在葡萄糖脑苷脂酶失活时明显积累了溶酶体糖脂，因此戈谢细胞似乎是血浆葡萄糖神经酰胺升高的主要来源。我们的研究结果表明，血浆葡萄糖神经酰胺可以作为 1 型戈谢病的生物标志物，但需要进一步研究其与戈谢病临床表现的关系。
