Orphanet Journal of Rare Diseases | Alterations in Sphingolipid Metabolism in Gaucher Disease

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This article systematically summarizes the alterations in sphingolipid metabolism in Gaucher disease (GD), revealing the heterogeneity of sphingolipid changes across different tissues and cells, as well as their potential pathological mechanisms, providing new insights into tissue-specific understanding of GD.

 

Literature Overview
This article, titled 'Alterations in Sphingolipid Metabolism in Gaucher Disease', was published in the Orphanet Journal of Rare Diseases. It reviews and summarizes 54 studies published between 1965 and 2024 on sphingolipid metabolism in Gaucher disease animal models, cell models, and human tissues. The article shows that in GD patients, lactosylceramide (DHC), trihexosylceramide (THC), and simple gangliosides (GM3, GM2, GM1, GD3, GD2) are generally elevated, while complex gangliosides (GT, GQ) are reduced. Sphingolipid alterations exhibit significant heterogeneity across tissues, and differences in current measurement techniques may affect result consistency. The article further explores compensatory mechanisms in sphingolipid metabolism and their impact on downstream signaling pathways, emphasizing the importance of tissue-specific analysis.

Background
Gaucher disease (GD) is a rare lysosomal storage disorder caused by loss-of-function mutations in the GBA1 gene, which encodes acid β-glucosidase (GCase). These mutations lead to impaired degradation of glucosylceramide (GlcCer) in the ceramide metabolic pathway, resulting in the accumulation of various sphingolipid metabolites in different tissues. Sphingolipids play critical roles in cell membrane structure and signal transduction, especially in neurons, where complex sphingolipids such as gangliosides are essential for synaptic plasticity, axonal growth, and myelination. Several mouse and ovine models of GD have been used in sphingolipid metabolism studies, but results often vary between models and measurement techniques. Additionally, compensatory mechanisms in sphingolipid metabolism (e.g., de novo synthesis, sphingomyelinase activation) may function differently across tissues and have not been fully elucidated in relation to neuropathological processes such as neuroinflammation and apoptosis. This article aims to systematically review the literature and summarize the patterns of sphingolipid alterations in GD, highlighting tissue-specific changes and potential pathological mechanisms to guide future research.

 

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Methods and Experiments
The researchers conducted a systematic literature review following the PRISMA-P guidelines, searching for 54 relevant studies published between 1965 and 2024 in PubMed, Scopus, and Web of Science. Inclusion criteria were: (1) studies involving GD patients, animal models, or cell models; (2) data on sphingolipid metabolism, including ceramide, lactosylceramide, gangliosides, etc.; (3) exclusion of data from patients who had received enzyme replacement or substrate reduction therapy to avoid confounding effects. The studies covered spleen, liver, skin, and brain tissues from GD patients, as well as various in vitro and in vivo models, to analyze the consistency and tissue-specificity of sphingolipid alterations. The researchers also evaluated how different measurement techniques (e.g., thin-layer chromatography, mass spectrometry) affect the consistency of sphingolipid data.

Key Findings and Perspectives

• In GD patients and animal models, lactosylceramide (DHC), trihexosylceramide (THC), and simple gangliosides (GM3, GM2, GM1, GD3, GD2) were elevated in 79% of the studies.
• Complex gangliosides (GT, GQ) were generally reduced (75%), while GD1a, GD1b, GQ1b showed inconsistent results across studies.
• Ceramide alterations varied significantly across tissues: elevated in the spleen (2/3 studies), mostly unchanged in the brain (82%), and highly variable in the skin, potentially due to GBA1 mutation subtypes and sphingolipid compensatory mechanisms.
• The variability in ceramide changes in the skin may reflect rapid sphingolipid turnover and individual differences in compensatory mechanisms. Moreover, different GD models (e.g., N370S and D409V mice) exhibited distinct sphingolipid alterations in skin phenotypes.
• Plasma and urine samples (liquid biopsies) show that GlcCer and GluSph can serve as stable biomarkers for GD, while DHC and ceramide levels are highly variable and may not be suitable as tissue surrogates.
• Compensatory mechanisms in sphingolipid metabolism (e.g., de novo synthesis, sphingomyelinase, ceramide recycling pathways) may be activated in different cells to maintain sphingolipid homeostasis, but their activation could further impact apoptosis, inflammation, and signaling pathways, leading to tissue-specific pathology.
• Gangliosides, particularly GM3 and GM1, are elevated in the brain tissues of GD patients, potentially contributing to neuroinflammation and synaptic dysfunction, while reduced levels of complex gangliosides (e.g., GT1b, GD1b) may impair neuronal maturation and myelination.
• Significant differences in sphingolipid metabolism exist between different neuronal types (e.g., cholinergic, dopaminergic), suggesting that region-specific analysis is critical for understanding the neuropathological mechanisms of GD.
• Sphingolipid alterations may contribute to neurodegeneration in GD by activating inflammasomes and affecting pathways such as Wnt/β-catenin, CASP, and NFкβ.
• While DHC consistently increases in neuroinflammatory conditions in GD, there is currently insufficient data to determine its changes in astrocytes or microglia, highlighting the need for future studies on sphingolipid alterations in specific glial cell types.

Significance and Future Directions
The article emphasizes the significant tissue heterogeneity in sphingolipid metabolism in GD, suggesting that different cell types may regulate sphingolipid homeostasis through distinct mechanisms. Future research should focus on individualized analysis of sphingolipid changes in different neuronal and glial cell types and explore the connections between sphingolipid dysregulation and pathological processes such as neuroinflammation, apoptosis, and autophagy. Additionally, the development of more sensitive sphingolipid analysis techniques, combined with models that enable real-time tracking of sphingolipid dynamics, will help elucidate the pathogenic mechanisms and potential therapeutic targets in GD.

 

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Conclusion
This article systematically reviews global sphingolipid alterations in Gaucher disease and reveals heterogeneous accumulation patterns across different tissues and cell models. Lactosylceramide (DHC) and simple gangliosides (e.g., GM3, GM2, GM1) are broadly elevated in neuronopathic forms of GD, whereas complex gangliosides (GT, GQ) are generally reduced. The variable changes in ceramide across tissues suggest cell-type-specific regulation of sphingolipid compensatory mechanisms. Additionally, sphingolipid dysregulation may contribute to GD pathology through activation of inflammation, apoptosis, and signaling pathways. However, most current studies are static and lack dynamic models for tracking sphingolipid changes over time. Future research should integrate high-resolution lipidomics with cell-type-specific analysis to further elucidate the functions and mechanisms of sphingolipids in GD, providing a theoretical basis for tissue-specific therapies.

 

Ashleigh Lake and Maria Fuller. Sphingolipids in Gaucher disease: a systematic review. Orphanet Journal of Rare Diseases.