Altered expression of ganglioside metabolizing enzymes results in GM3 ganglioside accumulation in cerebellar cells of a mouse model of juvenile neuronal ceroid lipofuscinosis

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dc.contributor.author Somogyi, Aleksandra
dc.contributor.author Petcherski, Anton
dc.contributor.author Beckert, Benedikt
dc.contributor.author Huebecker, Mylene
dc.contributor.author Priestman, David A.
dc.contributor.author Banning, Antje
dc.contributor.author Cotman, Susan L.
dc.contributor.author Platt, Frances M.
dc.contributor.author Ruonala, Mika O.
dc.contributor.author Tikkanen, Ritva
dc.date.accessioned 2018-06-15T11:47:16Z
dc.date.available 2018-06-15T11:47:16Z
dc.date.issued 2018
dc.identifier.citation Somogyi, A., Petcherski, A., Beckert, B., Huebecker, M., Priestman, D., Banning, A., Cotman, S., Platt, F., Ruonala, M. and Tikkanen, R. (2018) 'Altered expression of ganglioside metabolizing enzymes results in GM3 ganglioside accumulation in cerebellar cells of a mouse model of juvenile neuronal ceroid lipofuscinosis', International Journal of Molecular Sciences, 19(2), 625 (18pp). doi: 10.3390/ijms19020625 en
dc.identifier.volume 19
dc.identifier.issued 2
dc.identifier.startpage 1
dc.identifier.endpage 18
dc.identifier.issn 1422-0067
dc.identifier.uri http://hdl.handle.net/10468/6343
dc.identifier.doi 10.3390/ijms19020625
dc.description.abstract Juvenile neuronal ceroid lipofuscinosis (JNCL) is caused by mutations in the CLN3 gene. Most JNCL patients exhibit a 1.02 kb genomic deletion removing exons 7 and 8 of this gene, which results in a truncated CLN3 protein carrying an aberrant C-terminus. A genetically accurate mouse model (Cln3(ex7/8) mice) for this deletion has been generated. Using cerebellar precursor cell lines generated from wildtype and Cln3(ex7/8) mice, we have here analyzed the consequences of the CLN3 deletion on levels of cellular gangliosides, particularly GM3, GM2, GM1a and GD1a. The levels of GM1a and GD1a were found to be significantly reduced by both biochemical and cytochemical methods. However, quantitative high-performance liquid chromatography analysis revealed a highly significant increase in GM3, suggesting a metabolic blockade in the conversion of GM3 to more complex gangliosides. Quantitative real-time PCR analysis revealed a significant reduction in the transcripts of the interconverting enzymes, especially of -1,4-N-acetyl-galactosaminyl transferase 1 (GM2 synthase), which is the enzyme converting GM3 to GM2. Thus, our data suggest that the complex a-series gangliosides are reduced in Cln3(ex7/8) mouse cerebellar precursor cells due to impaired transcription of the genes responsible for their synthesis. en
dc.description.sponsorship Erasmus+ (Foundation for JNCL Research); National Institutes of Health (R01NS073813); Parkinson's UK (H-1501) en
dc.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher MDPI AG en
dc.relation.uri http://www.mdpi.com/1422-0067/19/2/625
dc.rights © 2018, the Authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). en
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.subject Batten disease en
dc.subject Neuronal ceroid lipofuscinosis en
dc.subject CLN3 en
dc.subject Lysosomal storage disorders en
dc.subject Glycosphingolipids en
dc.subject Gangliosides en
dc.title Altered expression of ganglioside metabolizing enzymes results in GM3 ganglioside accumulation in cerebellar cells of a mouse model of juvenile neuronal ceroid lipofuscinosis en
dc.type Article (peer-reviewed) en
dc.internal.authorcontactother Aleksandra Somogyi, Biochemistry and Cell Biology, University College Cork, Cork, Ireland. +353-21-490-3000 Email: aleksandra.somogyi@ucc.ie en
dc.internal.availability Full text available en
dc.description.version Published Version en
dc.contributor.funder Erasmus+
dc.contributor.funder NCL Stiftung
dc.contributor.funder BeatBatten Stichting
dc.contributor.funder National Institutes of Health
dc.contributor.funder Parkinson's UK
dc.description.status Peer reviewed
dc.identifier.journaltitle International Journal of Molecular Sciences en
dc.internal.IRISemailaddress aleksandra.somogyi@ucc.ie en
dc.identifier.articleid 625


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© 2018, the Authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). Except where otherwise noted, this item's license is described as © 2018, the Authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
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