Ganglioside GM2 catabolism is inhibited by storage compounds of mucopolysaccharidoses and by cationic amphiphilic drugs.

Abstract

The catabolism of ganglioside GM2 is dependent on the lysosomal enzyme β-hexosaminidase A and a supporting lipid transfer protein, the GM2 activator protein. A genetically based disturbance of GM2 catabolism, leads to several subtypes of the GM2 gangliosidosis: Tay-Sachs disease, Sandhoff disease, the AB-variant and the B1-variant, all of them having GM2 as major lysosomal storage compound. Further on it is known that the gangliosides GM2 and GM3 accumulate as secondary storage compounds in mucopolysaccharidoses, especially in Hunter disease, Hurler disease, Sanfilippo disease and Sly syndrome, with chondroitin sulfate as primary storage compound. The exact mechanism of ganglioside accumulation in mucopolysaccaridoses is still a matter of debate. Here, we show that chondroitin sulfate strongly inhibits the catabolism of membrane-bound GM2 by β-hexosaminidase A in presence of GM2 activator protein in vitro already at low micromolar concentrations. In contrast, hyaluronan, the major storage compound in mucopolysaccharidosis IX, a milder disease without secondary ganglioside accumulation, is a less effective inhibitor. On the other hand, hydrolysis of micellar-bound GM2 by β-hexosaminidase A without the assistance of GM2AP was not impeded by chondroitin sulfate implicating that the inhibition of GM2 hydrolysis by chondroitin sulfate is most likely based on an interaction with GM2AP, the GM2AP-GM2 complex or the GM2-carrying membranes. We also studied the influence of some cationic amphiphilic drugs (desipramine, chlorpromazine, imipramine and chloroquine), provoking drug induced phospholipidosis and found that all of them inhibited the hydrolysis of GM2 massively.

• Authors: Susi Anheuser, Bernadette Breiden, Konrad Sandhoff
• Journal: Molecular genetics and metabolism (Mol Genet Metab) 2019 Sep - Oct Vol. 128 Issue 1-2 Pg. 75-83 ISSN: 1096-7206 [Electronic] United States
• PMID: 31097363 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• Cations
• Glycosaminoglycans
• Surface-Active Agents
• G(M2) Ganglioside
• Chondroitin Sulfates

Topics

• Cations (chemistry)
• Chondroitin Sulfates (pharmacology)
• G(M2) Ganglioside (antagonists & inhibitors, metabolism)
• Glycosaminoglycans (pharmacology)
• Humans
• Hydrolysis (drug effects)
• Mucopolysaccharidoses (physiopathology)
• Surface-Active Agents (pharmacology)