{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T21:19:36Z","timestamp":1773868776357,"version":"3.50.1"},"reference-count":52,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2020,12,1]],"date-time":"2020-12-01T00:00:00Z","timestamp":1606780800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>\u03b2-hexosaminidase is an enzyme responsible for the degradation of gangliosides, glycans, and other glycoconjugates containing \u03b2-linked hexosamines that enter the lysosome. GM2 gangliosidoses, such as Tay-Sachs and Sandhoff, are lysosomal storage disorders characterized by \u03b2-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.<\/jats:p>","DOI":"10.1371\/journal.pone.0243006","type":"journal-article","created":{"date-parts":[[2020,12,1]],"date-time":"2020-12-01T20:55:22Z","timestamp":1606856122000},"page":"e0243006","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":9,"title":["Natural history study of glycan accumulation in large animal models of GM2 gangliosidoses"],"prefix":"10.1371","volume":"15","author":[{"given":"Catlyn","family":"Cavender","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Linley","family":"Mangini","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeremy L.","family":"Van Vleet","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carley","family":"Corado","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emma","family":"McCullagh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heather L.","family":"Gray-Edwards","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Douglas R.","family":"Martin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7811-4564","authenticated-orcid":true,"given":"Brett E.","family":"Crawford","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5027-2579","authenticated-orcid":true,"given":"Roger","family":"Lawrence","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2020,12,1]]},"reference":[{"issue":"2","key":"pone.0243006.ref001","doi-asserted-by":"crossref","first-page":"68","DOI":"10.2174\/1566523218666180404162622","article-title":"Genetics and Therapies for GM2 Gangliosidosis.","volume":"18","author":"MB Cachon-Gonzalez","year":"2018","journal-title":"Curr Gene Ther"},{"issue":"1\u20132","key":"pone.0243006.ref002","first-page":"1","article-title":"Lysosomal storage diseases","volume":"2","author":"CR Ferreira","year":"2017","journal-title":"Transl Sci Rare Dis."},{"key":"pone.0243006.ref003","doi-asserted-by":"crossref","first-page":"111","DOI":"10.2147\/TACG.S85354","article-title":"Animal models of GM2 gangliosidosis: utility and limitations","volume":"9","author":"CA Lawson","year":"2016","journal-title":"Appl Clin Genet"},{"key":"pone.0243006.ref004","volume-title":"Essentials of Glycobiology","author":"RL Schnaar","year":"2009"},{"key":"pone.0243006.ref005","doi-asserted-by":"crossref","first-page":"15057","DOI":"10.1038\/mtm.2015.57","article-title":"Construction of a hybrid beta-hexosaminidase subunit capable of forming stable homodimers that hydrolyze GM2 ganglioside in vivo","volume":"3","author":"MB Tropak","year":"2016","journal-title":"Mol Ther Methods Clin Dev"},{"issue":"5","key":"pone.0243006.ref006","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1016\/S0022-2836(03)00216-X","article-title":"Crystal structure of human beta-hexosaminidase B: understanding the molecular basis of Sandhoff and Tay-Sachs disease","volume":"327","author":"BL Mark","year":"2003","journal-title":"J Mol Biol"},{"issue":"1","key":"pone.0243006.ref007","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0005-2760(98)00057-5","article-title":"The GM2 activator protein, its roles as a co-factor in GM2 hydrolysis and as a general glycolipid transport protein","volume":"1393","author":"DJ Mahuran","year":"1998","journal-title":"Biochim Biophys Acta"},{"issue":"16","key":"pone.0243006.ref008","doi-asserted-by":"crossref","first-page":"12685","DOI":"10.1074\/jbc.M007970200","article-title":"Degradation of membrane-bound ganglioside GM2 by beta -hexosaminidase A. 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