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.authorSomogyi, Aleksandra
dc.contributor.authorPetcherski, Anton
dc.contributor.authorBeckert, Benedikt
dc.contributor.authorHuebecker, Mylene
dc.contributor.authorPriestman, David A.
dc.contributor.authorBanning, Antje
dc.contributor.authorCotman, Susan L.
dc.contributor.authorPlatt, Frances M.
dc.contributor.authorRuonala, Mika O.
dc.contributor.authorTikkanen, Ritva
dc.contributor.funderErasmus+
dc.contributor.funderNCL Stiftung
dc.contributor.funderBeatBatten Stichting
dc.contributor.funderNational Institutes of Health
dc.contributor.funderParkinson's UK
dc.date.accessioned2018-06-15T11:47:16Z
dc.date.available2018-06-15T11:47:16Z
dc.date.issued2018
dc.description.abstractJuvenile 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.sponsorshipErasmus+ (Foundation for JNCL Research); National Institutes of Health (R01NS073813); Parkinson's UK (H-1501)en
dc.description.statusPeer reviewed
dc.description.versionPublished Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.articleid625
dc.identifier.citationSomogyi, 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/ijms19020625en
dc.identifier.doi10.3390/ijms19020625
dc.identifier.endpage18
dc.identifier.issn1422-0067
dc.identifier.issued2
dc.identifier.journaltitleInternational Journal of Molecular Sciencesen
dc.identifier.startpage1
dc.identifier.urihttps://hdl.handle.net/10468/6343
dc.identifier.volume19
dc.language.isoenen
dc.publisherMDPI AGen
dc.relation.urihttp://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.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectBatten diseaseen
dc.subjectNeuronal ceroid lipofuscinosisen
dc.subjectCLN3en
dc.subjectLysosomal storage disordersen
dc.subjectGlycosphingolipidsen
dc.subjectGangliosidesen
dc.titleAltered expression of ganglioside metabolizing enzymes results in GM3 ganglioside accumulation in cerebellar cells of a mouse model of juvenile neuronal ceroid lipofuscinosisen
dc.typeArticle (peer-reviewed)en
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