Cargando…

Mechanism of Secondary Ganglioside and Lipid Accumulation in Lysosomal Disease

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 glycosphing...

Descripción completa

Detalles Bibliográficos
Autores principales: Breiden, Bernadette, Sandhoff, Konrad
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7178057/
https://www.ncbi.nlm.nih.gov/pubmed/32272755
http://dx.doi.org/10.3390/ijms21072566
_version_ 1783525367589371904
author Breiden, Bernadette
Sandhoff, Konrad
author_facet Breiden, Bernadette
Sandhoff, Konrad
author_sort Breiden, Bernadette
collection PubMed
description 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.
format Online
Article
Text
id pubmed-7178057
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-71780572020-04-28 Mechanism of Secondary Ganglioside and Lipid Accumulation in Lysosomal Disease Breiden, Bernadette Sandhoff, Konrad Int J Mol Sci Review 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. MDPI 2020-04-07 /pmc/articles/PMC7178057/ /pubmed/32272755 http://dx.doi.org/10.3390/ijms21072566 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Breiden, Bernadette
Sandhoff, Konrad
Mechanism of Secondary Ganglioside and Lipid Accumulation in Lysosomal Disease
title Mechanism of Secondary Ganglioside and Lipid Accumulation in Lysosomal Disease
title_full Mechanism of Secondary Ganglioside and Lipid Accumulation in Lysosomal Disease
title_fullStr Mechanism of Secondary Ganglioside and Lipid Accumulation in Lysosomal Disease
title_full_unstemmed Mechanism of Secondary Ganglioside and Lipid Accumulation in Lysosomal Disease
title_short Mechanism of Secondary Ganglioside and Lipid Accumulation in Lysosomal Disease
title_sort mechanism of secondary ganglioside and lipid accumulation in lysosomal disease
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7178057/
https://www.ncbi.nlm.nih.gov/pubmed/32272755
http://dx.doi.org/10.3390/ijms21072566
work_keys_str_mv AT breidenbernadette mechanismofsecondarygangliosideandlipidaccumulationinlysosomaldisease
AT sandhoffkonrad mechanismofsecondarygangliosideandlipidaccumulationinlysosomaldisease