title: 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.affiliation: Laboratory Centre, Kuopio University Hospital, FIN-70210 Kuopio, Finland.
authors.forename: Eira
authors.initials: E
authors.lastname: Kelo
authors.forename: Ulla
authors.initials: U
authors.lastname: Dunder
authors.forename: Ilkka
authors.initials: I
authors.lastname: Mononen
mesh_terms: D000818:Animals; D001216:Asparagine / Q000031:analogs & derivatives* / Q000032:analysis* / Q000378:metabolism; D054880:Aspartylglucosaminuria; D001227:Aspartylglucosylaminase / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D009844:Oligosaccharides / Q000032:analysis* / Q000378:metabolism
chemical_list: C500337:Man2GlcNAc2-Asn; D009844:Oligosaccharides; D001216:Asparagine; D001227:Aspartylglucosylaminase