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dc.contributor.authorCavender, Catlyn
dc.contributor.authorMangini, Linley
dc.contributor.authorVan Vleet, Jeremy L.
dc.contributor.authorCorado, Carley
dc.contributor.authorMcCullagh, Emma
dc.contributor.authorGray-Edwards, Heather L
dc.contributor.authorMartin, Douglas R.
dc.contributor.authorCrawford, Brett E.
dc.contributor.authorLawrence, Roger
dc.date2022-08-11T08:09:58.000
dc.date.accessioned2022-08-23T16:50:48Z
dc.date.available2022-08-23T16:50:48Z
dc.date.issued2020-12-01
dc.date.submitted2021-02-18
dc.identifier.citation<p>Cavender C, Mangini L, Van Vleet JL, Corado C, McCullagh E, Gray-Edwards HL, Martin DR, Crawford BE, Lawrence R. Natural history study of glycan accumulation in large animal models of GM2 gangliosidoses. PLoS One. 2020 Dec 1;15(12):e0243006. doi: 10.1371/journal.pone.0243006. PMID: 33259552; PMCID: PMC7707493. <a href="https://doi.org/10.1371/journal.pone.0243006">Link to article on publisher's site</a></p>
dc.identifier.issn1932-6203 (Linking)
dc.identifier.doi10.1371/journal.pone.0243006
dc.identifier.pmid33259552
dc.identifier.urihttp://hdl.handle.net/20.500.14038/41729
dc.description.abstractbeta-hexosaminidase is an enzyme responsible for the degradation of gangliosides, glycans, and other glycoconjugates containing beta-linked hexosamines that enter the lysosome. GM2 gangliosidoses, such as Tay-Sachs and Sandhoff, are lysosomal storage disorders characterized by beta-hexosaminidase deficiency and subsequent lysosomal accumulation of its substrate metabolites. These two diseases result in neurodegeneration and early mortality in children. A significant difference between these two disorders is the accumulation in Sandhoff disease of soluble oligosaccharide metabolites that derive from N- and O-linked glycans. In this paper we describe our results from a longitudinal biochemical study of a feline model of Sandhoff disease and an ovine model of Tay-Sachs disease to investigate the accumulation of GM2/GA2 gangliosides, a secondary biomarker for phospholipidosis, bis-(monoacylglycero)-phosphate, and soluble glycan metabolites in both tissue and fluid samples from both animal models. While both Sandhoff cats and Tay-Sachs sheep accumulated significant amounts of GM2 and GA2 gangliosides compared to age-matched unaffected controls, the Sandhoff cats having the more severe disease, accumulated larger amounts of gangliosides compared to Tay-Sachs sheep in their occipital lobes. For monitoring glycan metabolites, we developed a quantitative LC/MS assay for one of these free glycans in order to perform longitudinal analysis. The Sandhoff cats showed significant disease-related increases in this glycan in brain and in other matrices including urine which may provide a useful clinical tool for measuring disease severity and therapeutic efficacy. Finally, we observed age-dependent increasing accumulation for a number of analytes, especially in Sandhoff cats where glycosphingolipid, phospholipid, and glycan levels showed incremental increases at later time points without signs of peaking. This large animal natural history study for Sandhoff and Tay-Sachs is the first of its kind, providing insight into disease progression at the biochemical level. This report may help in the development and testing of new therapies to treat these disorders.
dc.language.isoen_US
dc.relation<p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=33259552&dopt=Abstract">Link to Article in PubMed</a></p>
dc.rightsCopyright: © 2020 Cavender et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectSphingolipids
dc.subjectSheep
dc.subjectOccipital lobe
dc.subjectTay-Sachs disease
dc.subjectCats
dc.subjectMetabolites
dc.subjectPhospholipids
dc.subjectUrine
dc.subjectAnimal Experimentation and Research
dc.subjectCongenital, Hereditary, and Neonatal Diseases and Abnormalities
dc.subjectNervous System Diseases
dc.subjectNutritional and Metabolic Diseases
dc.subjectVeterinary Medicine
dc.titleNatural history study of glycan accumulation in large animal models of GM2 gangliosidoses
dc.typeJournal Article
dc.source.journaltitlePloS one
dc.source.volume15
dc.source.issue12
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=5550&amp;context=oapubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/oapubs/4520
dc.identifier.contextkey21712576
refterms.dateFOA2022-08-23T16:50:48Z
html.description.abstract<p>beta-hexosaminidase is an enzyme responsible for the degradation of gangliosides, glycans, and other glycoconjugates containing beta-linked hexosamines that enter the lysosome. GM2 gangliosidoses, such as Tay-Sachs and Sandhoff, are lysosomal storage disorders characterized by beta-hexosaminidase deficiency and subsequent lysosomal accumulation of its substrate metabolites. These two diseases result in neurodegeneration and early mortality in children. A significant difference between these two disorders is the accumulation in Sandhoff disease of soluble oligosaccharide metabolites that derive from N- and O-linked glycans. In this paper we describe our results from a longitudinal biochemical study of a feline model of Sandhoff disease and an ovine model of Tay-Sachs disease to investigate the accumulation of GM2/GA2 gangliosides, a secondary biomarker for phospholipidosis, bis-(monoacylglycero)-phosphate, and soluble glycan metabolites in both tissue and fluid samples from both animal models. While both Sandhoff cats and Tay-Sachs sheep accumulated significant amounts of GM2 and GA2 gangliosides compared to age-matched unaffected controls, the Sandhoff cats having the more severe disease, accumulated larger amounts of gangliosides compared to Tay-Sachs sheep in their occipital lobes. For monitoring glycan metabolites, we developed a quantitative LC/MS assay for one of these free glycans in order to perform longitudinal analysis. The Sandhoff cats showed significant disease-related increases in this glycan in brain and in other matrices including urine which may provide a useful clinical tool for measuring disease severity and therapeutic efficacy. Finally, we observed age-dependent increasing accumulation for a number of analytes, especially in Sandhoff cats where glycosphingolipid, phospholipid, and glycan levels showed incremental increases at later time points without signs of peaking. This large animal natural history study for Sandhoff and Tay-Sachs is the first of its kind, providing insight into disease progression at the biochemical level. This report may help in the development and testing of new therapies to treat these disorders.</p>
dc.identifier.submissionpathoapubs/4520
dc.contributor.departmentDepartment of Radiology
dc.source.pagese0243006


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Copyright: © 2020 Cavender et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Except where otherwise noted, this item's license is described as Copyright: © 2020 Cavender et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.