Lake Ashleigh, Fuller Maria
Genetics and Molecular Pathology, SA Pathology at Women's and Children's Hospital, 72 King William Road, North Adelaide, 5006, Australia.
School of Biological Sciences, University of Adelaide, Adelaide, 5000, Australia.
Orphanet J Rare Dis. 2025 Nov 6;20(1):565. doi: 10.1186/s13023-025-04015-5.
Gaucher disease (GD) is a rare lysosomal disorder of sphingolipid catabolism, characterised by a block in the degradation of glucosylceramide (GlcCer) to ceramide. The resulting effect is lysosomal accumulation of GlcCer and its deacylated derivative, glucosylsphingosine. Secondary alterations in the sphingolipid metabolic pathway have been reported, including elevated concentrations of ceramide, lactosylceramide (dihexosylceramide (DHC)), and gangliosides, however, there are notable inconsistencies across different cell and tissue types and their relevance to GD pathology is not well-understood. Sphingolipids are crucial for the regulation of intra- and extracellular functions and different cell types have different requirements. For example, neurons have a high demand for complex sphingolipids due to their extensive membrane remodelling networks necessary for their communication role. We therefore performed literature searches of PubMed, Scopus, and Web of Science databases to coalesce reports of sphingolipids in different animal and cell models of GD, as well as human cells and tissues from 1965 to 2024, totalling 54 studies. We found that DHC, trihexosylceramide, and simple gangliosides, G, G, G, G, and G, were elevated in most reports (79%), complex G gangliosides were largely decreased (75%), and G, G, and G were inconsistently reported to be both increased and decreased in individual studies. Similarly, ceramide was highly discrepant between various cell and tissue types: spleen ceramide was elevated in two of three reports, brain ceramide was largely unchanged (82%), and ceramide concentrations in the skin were not consistent by any variable, including assay technique or GD sub-variant. Some of these discrepancies may be explained by biological variability and differences in methods used to measure sphingolipids, mass spectrometry being the most common, but it is clear that there are sphingolipid alterations in GD, which likely contribute to tissue-specific pathology. Evidence that sphingolipid metabolic regulation is variable across cells and tissues highlight the importance of characterising individual sphingolipid profiles on a model-to-model basis as a driving force behind cell pathology.
戈谢病（GD）是一种罕见的鞘脂分解代谢溶酶体疾病，其特征是葡萄糖脑苷脂（GlcCer）降解为神经酰胺的过程受阻。由此产生的影响是GlcCer及其脱酰基衍生物葡萄糖神经鞘氨醇在溶酶体中积累。据报道，鞘脂代谢途径存在继发性改变，包括神经酰胺、乳糖基神经酰胺（二己糖神经酰胺（DHC））和神经节苷脂浓度升高，然而，不同细胞和组织类型之间存在显著差异，其与GD病理学的相关性尚未得到很好的理解。鞘脂对于调节细胞内和细胞外功能至关重要，不同细胞类型有不同的需求。例如，神经元由于其广泛的膜重塑网络对其通讯作用至关重要，因此对复杂鞘脂有很高的需求。因此，我们对PubMed、Scopus和Web of Science数据库进行了文献检索，以汇总1965年至2024年期间不同动物和细胞模型的GD以及人类细胞和组织中鞘脂的报告，共计54项研究。我们发现，大多数报告（79%）中DHC、三己糖神经酰胺和简单神经节苷脂G、G、G、G和G升高，复杂的G神经节苷脂大多降低（75%），而在个别研究中，G、G和G的报告结果不一致，既有升高也有降低。同样，神经酰胺在各种细胞和组织类型之间差异很大：三份报告中有两份显示脾脏神经酰胺升高，大脑神经酰胺基本未变（82%），皮肤中神经酰胺浓度在任何变量（包括检测技术或GD亚型）方面都不一致。其中一些差异可能由生物学变异性和用于测量鞘脂的方法差异来解释，质谱法是最常用的方法，但很明显，GD中存在鞘脂改变，这可能导致组织特异性病理学。鞘脂代谢调节在不同细胞和组织中存在差异的证据凸显了在模型与模型基础上表征个体鞘脂谱作为细胞病理学背后驱动力的重要性。
