Sphingolipids in Gaucher disease: a systematic review.

Area of Science:

• Biochemistry
• Cell Biology
• Genetics

Background:

• Gaucher disease (GD) is a rare lysosomal storage disorder affecting sphingolipid metabolism.
• It's characterized by glucosylceramide (GlcCer) accumulation, leading to secondary alterations in other sphingolipids.
• Existing research shows inconsistencies in these secondary sphingolipid changes across different cell and tissue types.

Purpose of the Study:

• To systematically review and synthesize reported sphingolipid alterations in various Gaucher disease models and human tissues.
• To identify consistent and inconsistent patterns of sphingolipid changes, including ceramide, lactosylceramide (dihexosylceramide, DHC), and gangliosides.
• To highlight the importance of cell- and tissue-specific sphingolipid profiling in understanding GD pathology.

Main Methods:

• Conducted literature searches of PubMed, Scopus, and Web of Science databases.
• Included studies on animal and cell models of GD, as well as human cells and tissues.
• Analyzed data from 54 studies published between 1965 and 2024, focusing on sphingolipid concentrations.

Main Results:

• Dihexosylceramide (DHC), trihexosylceramide, and simple gangliosides (G_M3, G_M2, G_M1, G_D3, G_D2) were elevated in most reports (79%).
• Complex G_T gangliosides were decreased (75%), while others (G_D1a, G_D1b, G_Q1b) showed inconsistent changes.
• Ceramide levels displayed significant discrepancies across tissues: elevated in spleen, largely unchanged in brain, and inconsistent in skin.

Conclusions:

• Sphingolipid alterations in Gaucher disease are complex and exhibit significant cell- and tissue-specific variability.
• Discrepancies may stem from biological differences and methodological variations in sphingolipid measurement.
• Characterizing individual sphingolipid profiles is crucial for understanding cell pathology and developing targeted therapies for Gaucher disease.