{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T14:16:44Z","timestamp":1787235404079,"version":"build-2736575974"},"reference-count":37,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,11,30]],"date-time":"2023-11-30T00:00:00Z","timestamp":1701302400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Neurosci."],"abstract":"<jats:p>\n                    AB-Variant GM2 gangliosidosis (ABGM2) is a rare and lethal genetic disorder caused by mutations in the\n                    <jats:italic>GM2A<\/jats:italic>\n                    gene that lead to fatal accumulation of GM2 gangliosides (GM2) in neurons of the central nervous system (CNS).\n                    <jats:italic>GM2A<\/jats:italic>\n                    encodes a transport protein known as GM2 activator (GM2A) protein, which is essential for degrading GM2 into their GM3 form. ABGM2 presents in infantile-, juvenile-, and adult-onset forms; of the three, the infantile-onset is the most prominent, and by far the most severe, as evidenced by high levels of GM2 accumulation, widespread neurodegeneration, and death by the age of 4.\n                    <jats:italic>Gm2a<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice are commonly used as a model of ABGM2. These mice are characterized by phenotypes most representative of predicted adult-onset form of ABGM2, which include moderate GM2 accumulation and mild neurological defects. This mild phenotype has been attributed to compensation by alternative GM2 degradation pathways mediated by sialidase, neuraminidase 3 (NEU3), a pathway that is more prominent in mice than humans. To assess the extent to which NEU3 contributes to GM2 degradation, we generated double knock-out (\n                    <jats:italic>Gm2a<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    <jats:italic>Neu3<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    ) mice. Compellingly, these mice present with a clinical phenotype resembling that of a more severe ABGM2, including ataxia, reduced mobility and coordination, weight loss, poor body scores, and lethality by 6\u20137\u2009months. Furthermore, these phenotypes correlate with a dramatic increase in GM2 accumulation in the CNS compared to levels observed in either\n                    <jats:italic>Gm2a<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    or\n                    <jats:italic>Neu3<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice. Taken together, these studies, for the first-time, confirm that the mild neurological phenotype of\n                    <jats:italic>Gm2a<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice is due to compensatory activity on GM2 catabolism through an alternate breakdown pathway involving NEU3. These studies support the use of double knockout mice as a novel and highly relevant model for pre-clinical drug studies in a more severe form of ABGM2.\n                  <\/jats:p>","DOI":"10.3389\/fnmol.2023.1242814","type":"journal-article","created":{"date-parts":[[2023,11,30]],"date-time":"2023-11-30T02:28:17Z","timestamp":1701311297000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Characterization of a phenotypically severe animal model for human AB-Variant GM2 gangliosidosis"],"prefix":"10.3389","volume":"16","author":[{"given":"Natalie M.","family":"Deschenes","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camilyn","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prem","family":"Khanal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brianna M.","family":"Quinville","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex E.","family":"Ryckman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa","family":"Mitchell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexey V.","family":"Pshezhetsky","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jagdeep S.","family":"Walia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,11,30]]},"reference":[{"key":"ref1","unstructured":"Aky\u0131ld\u0131z DemirS.\n          2019"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"e1233","DOI":"10.1542\/peds.2011-0078","article-title":"Natural history of infantile GM2 gangliosidosis","volume":"128","author":"Bley","year":"2011","journal-title":"Pediatrics"},{"key":"ref3","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1007\/978-1-4613-1029-7_39","article-title":"The physiological roles of activator proteins for lysosomal glycolipid degradation","volume-title":"Lipid storage disorders","author":"Conzelmann","year":"1988"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1159\/000112160","article-title":"Biochemical basis of late-onset neurolipidoses","volume":"13","author":"Conzelmann","year":"1991","journal-title":"Dev. 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