Ganglioside Metabolism in Health and Disease

Sandhoff, Roger; Schulze, Heike; Sandhoff, Konrad

doi:10.1016/bs.pmbts.2018.01.002

Cited by 63 publications

(74 citation statements)

References 361 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…GM1 gangliosidosis is caused by a deficiency of the GM1 degrading lysosomal hydrolases acid β-galactosidase (EC 3.2.1.23). GM2 gangliosidoses are a group of disorders that result from defects in digestion of GG GM2 and related glycolipids by β-hexosaminidases (EC 3.2.1.52) and the GM2AP [8,25]. Both gangliosidoses are progressive neurodegenerative diseases previously diagnosed as "amaurotic idiocy" [16,26].…”

Section: Primary Storage Compounds In Gangliosidoses and Historical Amentioning

confidence: 99%

“…Another disease caused by mutations in the β-galactosidase gene GBL1 is mucopolysaccharidosis type IVB called Morquio type B disease. These mutations are different from those of GM1 gangliosidosis, and lead to a changed substrate specificity of the enzyme, thereby resulting in major accumulation of galactose containing keratan sulfate and oligosaccharides [5,25].…”

Section: Gm1 Gangliosidosismentioning

confidence: 99%

“…In the lysosomes, NEU1 is part of a multienzyme complex together with the protective protein/cathepsin A, a stabilizing protein for NEU1, and the GM1 hydrolyzing β-galactosidase [25]. Its inherited defects in GM1-gangliosidosis cause mainly a progressive accumulation of GG GM1 and its sialic acid free residue GA1 in the nervous system [8,14], triggering a neurodegenerative disease.…”

Section: Lysosomal Catabolism Of Ggsmentioning

confidence: 99%

“…Its inherited defects in GM1-gangliosidosis cause mainly a progressive accumulation of GG GM1 and its sialic acid free residue GA1 in the nervous system [8,14], triggering a neurodegenerative disease. In contrast to most membrane-bound sialidases, the soluble GM1-β-galactosidase needs an essential cofactor, a lipid-binding and transfer protein, either GM2AP or Sap B [25,41] to remove the terminal galactose residue from membrane-bound GM1 to generate membrane-bound GM2. Genetic defects of NEU1 trigger a sialidosis and impair the lysosomal catabolism of sialylated metabolites causing their accumulation [46], whereas inherited deficiencies of the stabilizing protein lead to a progressive accumulation of GM1, other glycolipids and oligosaccharides [47,48].…”

Section: Lysosomal Catabolism Of Ggsmentioning

confidence: 99%

See 3 more Smart Citations

Mechanism of Secondary Ganglioside and Lipid Accumulation in Lysosomal Disease

Breiden

Sandhoff

2020

IJMS

Self Cite

View full text Add to dashboard Cite

Gangliosidoses are caused by monogenic defects of a specific hydrolase or an ancillary sphingolipid activator protein essential for a specific step in the catabolism of gangliosides. Such defects in lysosomal function cause a primary accumulation of multiple undegradable gangliosides and glycosphingolipids. In reality, however, predominantly small gangliosides also accumulate in many lysosomal diseases as secondary storage material without any known defect in their catabolic pathway. In recent reconstitution experiments, we identified primary storage materials like sphingomyelin, cholesterol, lysosphingolipids, and chondroitin sulfate as strong inhibitors of sphingolipid activator proteins (like GM2 activator protein, saposin A and B), essential for the catabolism of many gangliosides and glycosphingolipids, as well as inhibitors of specific catabolic steps in lysosomal ganglioside catabolism and cholesterol turnover. In particular, they trigger a secondary accumulation of ganglioside GM2, glucosylceramide and cholesterol in Niemann-Pick disease type A and B, and of GM2 and glucosylceramide in Niemann-Pick disease type C. Chondroitin sulfate effectively inhibits GM2 catabolism in mucopolysaccharidoses like Hurler, Hunter, Sanfilippo, and Sly syndrome and causes a secondary neuronal ganglioside GM2 accumulation, triggering neurodegeneration. Secondary ganglioside and lipid accumulation is furthermore known in many more lysosomal storage diseases, so far without known molecular basis.

show abstract

Section: Primary Storage Compounds In Gangliosidoses and Historical Amentioning

confidence: 99%

Section: Gm1 Gangliosidosismentioning

confidence: 99%

Section: Lysosomal Catabolism Of Ggsmentioning

confidence: 99%

Section: Lysosomal Catabolism Of Ggsmentioning

confidence: 99%

See 2 more Smart Citations

Mechanism of Secondary Ganglioside and Lipid Accumulation in Lysosomal Disease

Breiden

Sandhoff

2020

IJMS

Self Cite

View full text Add to dashboard Cite

show abstract

“…On the other side, in relation to human cerebellum, glycomics was focused mainly on the compositional and structural analysis of lipid‐linked glycans and sialoglycans, in particular the sialylated glycosphingolipids known as gangliosides. This option was guided by the major role played by gangliosides in the central nervous system (CNS), not only as markers in the early diagnosis or prognosis of CNS diseases, but also as potential therapeutic agents and molecular fingerprints whose composition, being brain region‐ and cell‐type specific, changes during brain development, maturation, and aging.…”

Section: Introductionmentioning

confidence: 99%

Orbitrap mass spectrometry for monitoring the ganglioside pattern in human cerebellum development and aging

et al. 2020

View full text Add to dashboard Cite

We have developed here a superior approach based on high-resolution (HR) mass spectrometry (MS) for monitoring the changes occurring with development and aging in the composition and structure of cerebellar gangliosidome. The experiments were focused on the comparative screening and structural analysis of gangliosides expressed in fetal and aged cerebellum by Orbitrap MS with nanoelectrospray ionization (nanoESI) in the negative ion mode. The employed ultrahigh-resolution MS platform allowed the discrimination, without the need of previous separation, of 159 ions corresponding to 120 distinct species in the native ganglioside mixtures from fetal and aged cerebellar biopsies, many more than detected before, when MS platforms of lower resolution were employed. A number of gangliosides, in particular polysialylated belonging to GT, GQ, GP, and GS classes, modified by O-fucosylation, O-acetylation, or CH 3 COO − were discovered here, for the first time in human cerebellum. These components, found differently expressed in fetal and aged tissues, indicated that the ganglioside profile in cerebellum is development stage-and agespecific. Following the fragmentation analysis by high-energy collision-induced dissociation (HCD) tandem MS (MS/MS), we have also observed that the intimate structure of certain compounds has not changed during the development and aging of the brain, an aspect which could open new directions in the investigation of ganglioside biomarkers in cerebellar tissue.

show abstract

Emerging concepts of ganglioside metabolism

Sandhoff

2018

FEBS Letters

Self Cite

View full text Add to dashboard Cite

Gangliosides (GGs) are sialic acid-containing glycosphingolipids (GSLs) and major membrane components enriched on cellular surfaces. Biosynthesis of mammalian GGs starts at the cytosolic leaflet of endoplasmic reticulum (ER) membranes with the formation of their hydrophobic ceramide anchors. After intracellular ceramide transfer to Golgi and trans-Golgi network (TGN) membranes, anabolism of GGs, as well as of other GSLs, is catalyzed by membrane-spanning glycosyltransferases (GTs) along the secretory pathway. Combined activity of only a few promiscuous GTs allows for the formation of cell-type-specific glycolipid patterns. Following an exocytotic vesicle flow to the cellular plasma membranes, GGs can be modified by metabolic reactions at or near the cellular surface. For degradation, GGs are endocytosed to reach late endosomes and lysosomes. Whereas membrane-spanning enzymes of the secretory pathway catalyze GSL and GG formation, a cooperation of soluble glycosidases, lipases and lipid-binding cofactors, namely the sphingolipid activator proteins (SAPs), act as the main players of GG and GSL catabolism at intralysosomal luminal vesicles (ILVs).

show abstract

Ganglioside Metabolism in Health and Disease

Cited by 63 publications

References 361 publications

Mechanism of Secondary Ganglioside and Lipid Accumulation in Lysosomal Disease

Mechanism of Secondary Ganglioside and Lipid Accumulation in Lysosomal Disease

Orbitrap mass spectrometry for monitoring the ganglioside pattern in human cerebellum development and aging

Emerging concepts of ganglioside metabolism

Contact Info

Product

Resources

About