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Altered Expression of Ganglioside Metabolizing Enzymes Results in GM3 Ganglioside Accumulation in Cerebellar Cells of a Mouse Mo

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Altered Expression of Ganglioside Metabolizing Enzymes Results in GM3 Ganglioside Accumulation in Cerebellar Cells of a Mouse Mo International Journal of Molecular Sciences Article Altered Expression of Ganglioside Metabolizing Enzymes Results in GM3 Ganglioside Accumulation in Cerebellar Cells of a Mouse Model of Juvenile Neuronal Ceroid Lipofuscinosis Aleksandra Somogyi 1,†,‡, Anton Petcherski 1,†,§, Benedikt Beckert 2, Mylene Huebecker 3, David A. Priestman 3, Antje Banning 2, Susan L. Cotman 4, Frances M. Platt 3, Mika O. Ruonala 1,*,|| and Ritva Tikkanen 2,* ID 1 Center for Membrane Proteomics, Goethe University of Frankfurt, 60438 Frankfurt am Main, Germany; [email protected] (A.S.); [email protected] (A.P.) 2 Institute of Biochemistry, Medical Faculty, University of Giessen, Friedrichstrasse 24, 35292 Giessen, Germany; [email protected] (B.B.); [email protected] (A.B.) 3 Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK; [email protected] (M.H.); [email protected] (D.A.P.); [email protected] (F.M.P.) 4 Center for Genomic Medicine, Department of Neurology, Massachusetts General Hospital Research Institute, Harvard Medical School, 185 Cambridge Street, Boston, MA 02114, USA; [email protected] * Correspondence: [email protected] (M.O.R.); [email protected] (R.T.); Tel.: +49-641-9947 420 (R.T.) † These authors contributed equally to this work. ‡ Present Address: School of Biochemistry and Cell Biology, BioSciences Insitute, University College Cork, Cork T12YT20, Ireland. § Present Address: Division of Endocrinology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, 650 Charles E Young Drive S, Los Angeles, CA 90095, USA. k Present Address: Image Computing & Information Technologies, Kapersburgstrasse 12, 60437 Frankfurt, Germany. Received: 1 February 2018; Accepted: 19 February 2018; Published: 22 February 2018 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 (Cln3Dex7/8 mice) for this deletion has been generated. Using cerebellar precursor cell lines generated from wildtype and Cln3Dex7/8 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 β-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 Cln3Dex7/8 mouse cerebellar precursor cells due to impaired transcription of the genes responsible for their synthesis. Keywords: Batten disease; neuronal ceroid lipofuscinosis; CLN3; lysosomal storage disorders; glycosphingolipids; gangliosides Int. J. Mol. Sci. 2018, 19, 625; doi:10.3390/ijms19020625 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2018, 19, 625 2 of 18 1. Introduction Int. J. Mol. Sci. 2018, 19, x 2 of 17 Juvenile neuronal ceroid lipofuscinosis (JNCL) is a lysosomal storage disorder caused by mutations1. Introduction in the CLN3 gene. Most JNCL patients worldwide are homo- or heterozygous for a deletion that removesJuvenile exons neuronal 7 and 8ceroid together lipofuscinosis with thebridging (JNCL) is intron. a lysosomal A genetically storage authenticdisorder caused mouse by model for thismutations mutation in the has CLN3 been gene. generated, Most JNCL and patients it has worldwide been shown are to homo- recapitulate or heterozygous many of for the a deletion pathogenic featuresthat ofremoves human exons JNCL 7 and disease 8 together [1–6]. with One the of bridging the first intron. symptoms A genetically in JNCL authentic patients mouse is visual model system impairmentfor this mutation that frequently has been manifests generated, atand the it has age been of 5—8 shown years to recapitulate and leads tomany blindness of the pathogenic due to retinal degeneration.features of Withinhuman JNCL the first disease decade [1–6]. of One life, of the the patients’ first symptoms mental in and JNCL physical patients capabilities is visual system continue impairment that frequently manifests at the age of 5—8 years and leads to blindness due to retinal to decline, and epileptic seizures become evident. In addition to the central nervous system, JNCL degeneration. Within the first decade of life, the patients’ mental and physical capabilities continue patientsto decline, also exhibit and epileptic pathologic seizures features become in theevident. cardiac In addition and immune to the central systems. nervous Towards system, the JNCL end of the secondpatients decade also of exhibit life, many pathologic patients features rapidly in the deteriorate cardiac and and immune become systems. wheelchair Towards bound, the end with of the death usuallysecond occurring decade byof life, the agemany of patients 25. rapidly deteriorate and become wheelchair bound, with death Theusually gene occurring product, by the CLN3 age of protein, 25. is a transmembrane protein that is predicted to span the membraneThe 6 times,gene product, with both CLN3 N- protein, and C-terminus is a transmembrane residing inprotein the cytosol that is [predicted7,8]. Although to span the the exact molecularmembrane function 6 times, of the with CLN3 both protein N- and has C-terminus not been re conclusivelysiding in the verified, cytosol [7,8]. it has Although been linked the toexact various cellularmolecular processes function such of as the autophagy, CLN3 protein lysosomal has not pH, been vesicular conclusively trafficking verified, and it has cation been homeostasis linked to in various cellular processes such as autophagy, lysosomal pH, vesicular trafficking and cation lysosomes [2,4,9,10]. Furthermore, the CLN3 protein has been shown to be associated with cell homeostasis in lysosomes [2,4,9,10]. Furthermore, the CLN3 protein has been shown to be associated proliferation, control of cell cycle and apoptosis. However, it is not clear if these phenotypic features with cell proliferation, control of cell cycle and apoptosis. However, it is not clear if these phenotypic are directlyfeatures caused are directly by an caused impairment by an of impairment CLN3 protein of CLN3 function protein or if function they represent or if they secondary represent effects. Glycosphingolipidssecondary effects. (GSLs) are important glycan structures mainly residing at the cell surface, especiallyGlycosphingolipids in neuronal cells. (GSLs) GSLs are comprise important ceramide glycan structures linked to mainly a varying residing number at the of cell sugar surface, residues. Gangliosidesespecially arein neuronal a subgroup cells. ofGSLs GSLs, comprise distinguished ceramide linked by the to presence a varying of number sialic acidof sugar residues, residues. mainly N-acetylneuraminicGangliosides are a acid subgroup in humans of GSLs, [11 distinguished,12]. The biosynthesis by the presence pathway of sialic and acid the residues, structures mainly of the a-seriesN-acetylneuraminic gangliosides with acid their in humans synthesizing [11,12]. enzymesThe biosynthesis are shown pathway in Figure and the1, andstructures the genes of the and a- the respectiveseries enzymesgangliosides are with summarized their synthesizing in Table1 enzyme. GM3 iss are synthesized shown in Figure from lactosylceramide 1, and the genes and (LacCer) the by respective enzymes are summarized in Table 1. GM3 is synthesized from lactosylceramide (LacCer) the enzyme LacCer sialyltransferase (GM3 synthase) and is the precursor for the a-series gangliosides. by the enzyme LacCer sialyltransferase (GM3 synthase) and is the precursor for the a-series Conversion to GM2 takes place by the action of GM2 synthase (GalNAc transferase). Addition of gangliosides. Conversion to GM2 takes place by the action of GM2 synthase (GalNAc transferase). a galactoseAddition residue of a galactose to GM2 residue by galactosyltransferase to GM2 by galactosyltransferase 2 (GM1 synthase) 2 (GM1 synthase) results in results GM1a in ganglioside, GM1a whichganglioside, can further which be converted can further into be GD1a converted upon terminalinto GD1a sialylation upon terminal by a sialyltransferase sialylation by (GD1aa synthase).sialyltransferase GT1a can (GD1a be synthesized synthase). from GT1a GD1a can be by synthesized sialylation from by GT1a GD1a synthase. by sialylation The same by GT1a enzymes are responsiblesynthase. The for same the synthesisenzymes are of theresponsible b- and c-seriesfor the synthesis gangliosides of the whereb- and thec-series synthesis gangliosides precursors arisewhere from the GM3 synthesis by further precursors sialylation. arise from For GM3 a detailed by further description sialylation. ofFor the a detailed structures description of the of b- and c-series,the structures please refer of the to theb- and review c-series, by Daniottiplease refer and to Iglesias-Bartolomthe review by Daniottié [13 and].
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