Show simple item record

dc.contributor.authorLawrence, Rogerpt_BR
dc.contributor.authorvan Vleet, Jeremy L.pt_BR
dc.contributor.authorMangini, Linleypt_BR
dc.contributor.authorHarris, Adampt_BR
dc.contributor.authorMartin, Nathan T.pt_BR
dc.contributor.authorClark, Wyatt T.pt_BR
dc.contributor.authorChandriani, Sanjaypt_BR
dc.contributor.authorLeBowitz, Jonathan H.pt_BR
dc.contributor.authorGiugliani, Robertopt_BR
dc.contributor.authorD'Azzo, Alessandrapt_BR
dc.contributor.authorYogalingam, Gouript_BR
dc.contributor.authorCrawford, Brett E.pt_BR
dc.date.accessioned2019-12-28T04:01:26Zpt_BR
dc.date.issued2019pt_BR
dc.identifier.issn2214-4269pt_BR
dc.identifier.urihttp://hdl.handle.net/10183/203968pt_BR
dc.description.abstractIntroduction: GM1 gangliosidosis is a rare autosomal recessive genetic disorder caused by the disruption of the GLB1 gene that encodes β-galactosidase, a lysosomal hydrolase that removes β-linked galactose from the non-reducing end of glycans. Deficiency of this catabolic enzyme leads to the lysosomal accumulation of GM1 and its asialo derivative GA1 in β-galactosidase deficient patients and animal models. In addition to GM1 and GA1, there are other glycoconjugates that contain β-linked galactose whose metabolites are substrates for β-galactosidase. For example, a number of N-linked glycan structures that have galactose at their non-reducing end have been shown to accumulate in GM1 gangliosidosis patient tissues and biological fluids. Objective: In this study, we attempt to fully characterize the broad array of GLB1 substrates that require GLB1 for their lysosomal turnover. Results: Using tandem mass spectrometry and glycan reductive isotope labeling with data-dependent mass spectrometry, we have confirmed the accumulation of glycolipids (GM1 and GA1) and N-linked glycans with terminal beta-linked galactose. We have also discovered a novel set of core 1 and 2 O-linked glycan metabolites, many of which are part of structurally-related isobaric series that accumulate in disease. In the brain of GLB1 null mice, the levels of these glycan metabolites increased along with those of both GM1 and GA1 as a function of age. In addition to brain tissue, we found elevated levels of both N-linked and O-linked glycan metabolites in a number of peripheral tissues and in urine. Both brain and urine samples from human GM1 gangliosidosis patients exhibited large increases in steady state levels for the same glycan metabolites, demonstrating their correlation with this disease in humans as well. Conclusions: Our studies illustrate that GLB1 deficiency is not purely a ganglioside accumulation disorder, but instead a broad oligosaccharidosis that include representatives of many β-linked galactose containing glycans and glycoconjugates including glycolipids, N-linked glycans, and various O-linked glycans. Accounting for all β-galactosidase substrates that accumulate when this enzyme is deficient increases our understanding of this severe disorder by identifying metabolites that may drive certain aspects of the disease and may also serve as informative disease biomarkers to fully evaluate the efficacy of future therapies.en
dc.format.mimetypeapplication/pdfpt_BR
dc.language.isoengpt_BR
dc.relation.ispartofMolecular genetics and metabolism reports. New York. vol. 21 (Dec. 2019), 100524, 17 f.pt_BR
dc.rightsOpen Accessen
dc.subjectGM1 gangliosidosisen
dc.subjectGangliosidose GM1pt_BR
dc.subjectGLB1en
dc.subjectbeta-Galactosidasept_BR
dc.subjectBeta-galactosidaseen
dc.subjectBiomarcadorespt_BR
dc.subjectGlycan metabolitesen
dc.subjectDisease biomarkersen
dc.subjectGlycoanalysisen
dc.titleCharacterization of glycan substrates accumulating in GM1 Gangliosidosispt_BR
dc.typeArtigo de periódicopt_BR
dc.identifier.nrb001109125pt_BR
dc.type.originEstrangeiropt_BR


Files in this item

Thumbnail
   

This item is licensed under a Creative Commons License

Show simple item record