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. 2024 Apr 22;18:1391413. doi: 10.3389/fnins.2024.1391413

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Copyright © 2024 Itokazu and Terry.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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Metabolic pathways and functional roles of glycosphingolipids, including gangliosides. (A) Metabolic pathways and structure. Cer ceramide, CST cerebroside sulfotransferase (Gal3st1, sulfatide synthase), GalNAc-T N-acetylgalactosaminyltransferase I (B4galnt1, GA2/GM2/GD2/GT2 synthase), GalT-I galactosyltransferase I (B4galT5 & B4galt6, lactosylceramide synthase), GalT-II galactosyltransferase II (B3galt4, GA1/GM1/GD1b/GT1c synthase), GalT-III galactosyltransferase III (Ugt8a, galactosylceramide synthase), GlcT glucosyltransferase (Ugcg, glucosylceramide synthase), ST-I sialyltransferase I (St3gal5, GM3 synthase), ST-II sialyltransferase II (St8Sia1, GD3 synthase), ST-III sialyltransferase III (St8Sia3, GT3 synthase), ST-IV sialyltransferase IV (St3gal2, GM1b/GD1a/GT1b/GQ1c synthase), ST-V sialyltransferase V (St8sia5, GD1c/GT1a/GQ1b/GP1c synthase), ST-VII sialyltransferase VII (St6galnac6, GD1aα/GT1aα/GQ1bα/GP1cα-synthase). Official symbols of genes are represented in italics in this figure legend. GD3 is the most abundant ganglioside in neural stem cells (NSCs). c-Series gangliosides are A2B5 antigens. GM1, GD1a, GD1b, and GT1b are the most abundant ganglioside species in adult mammalian brain and neurons. Oligodendrocyte markers O1 and O4 are GalCer and sulfatide, respectively. GT1aα and GQ1bα are cholinergic-specific antigens (Chol-1α). (B) Examples of ganglioside functions. Without GD3, Drp1 levels are increased, and aberrant mitochondrial fragmentation is augmented. GD3 suppresses p21 expression and maintains p27 expression in NSCs. Gangliosides bind to the neurotrophic factor receptors to regulate their signalings. GM1 promotes integrin signaling for cell protrusion and migration. Gangliosides prevent and even reduce the accumulation of toxic proteins [e.g., amyloid-beta peptides (Aβs) and alpha-synuclein (α-syn)] in neurodegenerative diseases. Nuclear GM1 epigenetically promotes neuronal gene expression to sustain healthy neuronal functions. Elevation of GM1 levels induces Ca influx and neurite outgrowth. The listed in the figure is a limited examples, but, ganglioside-based multifunctional therapy is promising.