Massive accumulation of Man2GlcNAc2-Asn in nonneuronal tissues of glycosylasparaginase-deficient mice and its removal by enzyme replacement therapy.

Abstract

Aspartylglycosaminuria (AGU) is caused by deficient enzymatic activity of glycosylasparaginase (GA). The disease is characterized by accumulation of aspartylglucosamine (GlcNAc-Asn) and other glycoasparagines in tissues and body fluids of AGU patients and in an AGU mouse model. In the current study, we characterized a glycoasparagine carrying the tetrasaccharide moiety of alpha-D-Man-(1-->6)-beta-D-Man-(1-->4)-beta-D-GlcNAc-(1-->4)-beta-D-GlcNAc-(1-->N)-Asn (Man2GlcNAc2-Asn) in urine of an AGU patient and also in the tissues of the AGU mouse model. Quantitative analysis demonstrated a massive accumulation of the compound especially in nonneuronal tissues of the AGU mice, in which the levels of Man2GlcNAc2-Asn were typically 30-87% of those of GlcNAc-Asn. The highest level of Man2GlcNAc2-Asn was found in the liver, spleen, and heart tissues of the AGU mice, the respective amounts being 87%, 76%, and 57% of the GlcNAc-Asn levels. In the brain tissue of AGU mice the Man2GlcNAc2-Asn storage was only 9% of that of GlcNAc-Asn. In contrast to GlcNAc-Asn, the storage of Man2GlcNAc2-Asn markedly increased in the liver and spleen tissues of AGU mice as they grew older. Enzyme replacement therapy with glycosylasparaginase for 3.5 weeks reduced the amount of Man2GlcNAc2-Asn by 66-97% in nonneuronal tissues, but only by 13% in the brain tissue of the AGU mice. In conclusion, there is evidence for a role for storage of glycoasparagines other than aspartylglucosamine in the pathogenesis of AGU, and this possibility should be taken into consideration in the treatment of the disease.

• Authors: Eira Kelo, Ulla Dunder, Ilkka Mononen
• Journal: Glycobiology (Glycobiology) Vol. 15 Issue 1 Pg. 79-85 (Jan 2005) ISSN: 0959-6658 [Print] England
• PMID: 15342551 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Man2GlcNAc2-Asn
• Oligosaccharides
• Asparagine
• Aspartylglucosylaminase

Topics

• Animals
• Asparagine (analogs & derivatives, analysis, metabolism)
• Aspartylglucosaminuria
• Aspartylglucosylaminase (genetics, metabolism, therapeutic use)
• Liver (metabolism)
• Mice
• Mice, Knockout
• Neurons (metabolism)
• Oligosaccharides (analysis, metabolism)