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01.03.2014 | Original Article

Non-specific accumulation of glycosphingolipids in GNE myopathy

verfasst von: Katherine A. Patzel, Tal Yardeni, Erell Le Poëc-Celic, Petcharat Leoyklang, Heidi Dorward, Dominic S. Alonzi, Nikolay V. Kukushkin, Bixue Xu, Yongmin Zhang, Matthieu Sollogoub, Yves Blériot, William A. Gahl, Marjan Huizing, Terry D. Butters

Erschienen in: Journal of Inherited Metabolic Disease | Ausgabe 2/2014

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Abstract

Background

UDP-GlcNAc 2-epimerase/ManNAc 6-kinase (GNE) is a bifunctional enzyme responsible for the first committed steps in the synthesis of sialic acid, a common terminal monosaccharide in both protein and lipid glycosylation. GNE mutations are responsible for a rare autosomal recessive neuromuscular disorder, GNE myopathy (also called hereditary inclusion body myopathy). The connection between the impairment of sialic acid synthesis and muscle pathology in GNE myopathy remains poorly understood.

Methods

Glycosphingolipid (GSL) analysis was performed by HPLC in multiple models of GNE myopathy, including patients’ fibroblasts and plasma, control fibroblasts with inhibited GNE epimerase activity through a novel imino sugar, and tissues of Gne^M712T/M712T knock-in mice.

Results

Not only neutral GSLs, but also sialylated GSLs, were significantly increased compared to controls in all tested models of GNE myopathy. Treatment of GNE myopathy fibroblasts with N-acetylmannosamine (ManNAc), a sialic acid precursor downstream of GNE epimerase activity, ameliorated the increased total GSL concentrations.

Conclusion

GNE myopathy models have increased total GSL concentrations. ManNAc supplementation results in decrease of GSL levels, linking abnormal increase of total GSLs in GNE myopathy to defects in the sialic acid biosynthetic pathway. These data advocate for further exploring GSL concentrations as an informative biomarker, not only for GNE myopathy, but also for other disorders of sialic acid metabolism.

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Al-Rawi S, Hinderlich S, Reutter W, Giannis A (2004) Synthesis and biochemical properties of reversible inhibitors of UDP-N-acetylglucosamine 2-epimerase. Angew Chem Int Ed Engl 43:4366–4370PubMedCrossRef

Alonzi DS, Butters TD (2011) Therapeutic targets for inhibitors of glycosylation. Chimia (Aarau) 65:35–39CrossRef

Amsili S, Zer H, Hinderlich S et al (2008) UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) binds to alpha-actinin 1: novel pathways in skeletal muscle? PLoS One 3:e2477PubMedCentralPubMedCrossRef

Argov Z, Yarom R (1984) “Rimmed vacuole myopathy” sparing the quadriceps. A unique disorder in Iranian Jews. J Neurol Sci 64:33–43PubMedCrossRef

Askanas V, Alvarez RB, Engel WK (1993) beta-Amyloid precursor epitopes in muscle fibers of inclusion body myositis. Ann Neurol 34:551–560PubMedCrossRef

Askanas V, Engel WK (1995) New advances in the understanding of sporadic inclusion-body myositis and hereditary inclusion-body myopathies. Curr Opin Rheumatol 7:486–496PubMedCrossRef

Butters TD, Dwek RA, Platt FM (2000) Inhibition of glycosphingolipid biosynthesis: application to lysosomal storage disorders. Chem Rev 100:4683–4696PubMedCrossRef

Chou HH, Takematsu H, Diaz S et al (1998) A mutation in human CMP-sialic acid hydroxylase occurred after the Homo-Pan divergence. Proc Natl Acad Sci U S A 95:11751–11756PubMedCentralPubMedCrossRef

Eisenberg I, Avidan N, Potikha T et al (2001) The UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase gene is mutated in recessive hereditary inclusion body myopathy. Nat Genet 29:83–87PubMedCrossRef

Eisenberg I, Grabov-Nardini G, Hochner H et al (2003) Mutations spectrum of GNE in hereditary inclusion body myopathy sparing the quadriceps. Hum Mutat 21:99PubMedCrossRef

Eskelinen EL (2006) Roles of LAMP-1 and LAMP-2 in lysosome biogenesis and autophagy. Mol Aspects Med 27:495–502PubMedCrossRef

Galeano B, Klootwijk R, Manoli I et al (2007) Mutation in the key enzyme of sialic acid biosynthesis causes severe glomerular proteinuria and is rescued by N-acetylmannosamine. J Clin Invest 117:1585–1594PubMedCentralPubMedCrossRef

Ghaderi D, Strauss HM, Reinke S et al (2007) Evidence for dynamic interplay of different oligomeric states of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase by biophysical methods. J Mol Biol 369:746–758PubMedCrossRef

Hinderlich S, Berger M, Keppler OT, Pawlita M, Reutter W (2001) Biosynthesis of N-acetylneuraminic acid in cells lacking UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase. Biol Chem 382:291–297PubMedCrossRef

Hinderlich S, Stasche R, Zeitler R, Reutter W (1997) A bifunctional enzyme catalyzes the first two steps in N-acetylneuraminic acid biosynthesis of rat liver. Purification and characterization of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase. J Biol Chem 272:24313–24318PubMedCrossRef

Huizing M, Krasnewich DM (2009) Hereditary inclusion body myopathy: a decade of progress. Biochim Biophys Acta 1792:881–887PubMedCentralPubMedCrossRef

Huwiler A, Kolter T, Pfeilschifter J, Sandhoff K (2000) Physiology and pathophysiology of sphingolipid metabolism and signaling. Biochim Biophys Acta 1485:63–99PubMedCrossRef

Jones MB, Teng H, Rhee JK et al (2004) Characterization of the cellular uptake and metabolic conversion of acetylated N-acetylmannosamine (ManNAc) analogues to sialic acids. Biotechnol Bioeng 85:394–405PubMedCrossRef

Kakani S, Yardeni T, Poling J et al (2012) The Gne M712T mouse as a model for human glomerulopathy. Am J Pathol 180:1431–1440PubMedCentralPubMedCrossRef

Keppler OT, Hinderlich S, Langner J et al (1999) UDP-GlcNAc 2-epimerase: a regulator of cell surface sialylation. Science 284:1372–1376PubMedCrossRef

Kershaw DB, Beck SG, Wharram BL et al (1997) Molecular cloning and characterization of human podocalyxin-like protein. Orthologous relationship to rabbit PCLP1 and rat podocalyxin. J Biol Chem 272:15708–15714PubMedCrossRef

Krause S, Hinderlich S, Amsili S et al (2005) Localization of UDP-GlcNAc 2-epimerase/ManAc kinase (GNE) in the Golgi complex and the nucleus of mammalian cells. Exp Cell Res 304:365–379PubMedCrossRef

Li H, Marcelo F, Bello C et al (2009) Design and synthesis of acetamido tri- and tetra-hydroxyazepanes: potent and selective beta-N-acetylhexosaminidase inhibitors. Bioorg Med Chem 17:5598–5604PubMedCrossRef

Lucka L, Krause M, Danker K, Reutter W, Horstkorte R (1999) Primary structure and expression analysis of human UDP-N-acetyl-glucosamine-2-epimerase/N-acetylmannosamine kinase, the bifunctional enzyme in neuraminic acid biosynthesis. FEBS Lett 454:341–344PubMedCrossRef

Malicdan MC, Nishino I (2012) Autophagy in lysosomal myopathies. Brain Pathol 22:82–88PubMedCrossRef

Malicdan MC, Noguchi S, Hayashi YK, Nonaka I, Nishino I (2009) Prophylactic treatment with sialic acid metabolites precludes the development of the myopathic phenotype in the DMRV-hIBM mouse model. Nat Med 15:690–695PubMedCrossRef

Malicdan MC, Noguchi S, Nishino I (2007a) Autophagy in a mouse model of distal myopathy with rimmed vacuoles or hereditary inclusion body myopathy. Autophagy 3:396–398PubMed

Malicdan MC, Noguchi S, Nonaka I, Hayashi YK, Nishino I (2007b) A Gne knockout mouse expressing human GNE D176V mutation develops features similar to distal myopathy with rimmed vacuoles or hereditary inclusion body myopathy. Hum Mol Genet 16:2669–2682PubMedCrossRef

Malicdan MC, Noguchi S, Nonaka I, Saftig P, Nishino I (2008) Lysosomal myopathies: an excessive build-up in autophagosomes is too much to handle. Neuromuscul Disord 18:521–529PubMedCrossRef

Malicdan MC, Noguchi S, Tokutomi T et al (2012) Peracetylated N-acetylmannosamine, a synthetic sugar molecule, efficiently rescues muscle phenotype and biochemical defects in mouse model of sialic acid-deficient myopathy. J Biol Chem 287:2689–2705PubMedCentralPubMedCrossRef

Nemunaitis G, Jay CM, Maples PB et al (2011) Hereditary inclusion body myopathy: single patient response to intravenous dosing of GNE gene Lipoplex. Hum Gene Ther 22:1331–1341PubMedCentralPubMedCrossRef

Nemunaitis G, Maples PB, Jay C et al (2010) Hereditary inclusion body myopathy: single patient response to GNE gene Lipoplex therapy. J Gene Med 12:403–412PubMedCrossRef

Neville DC, Alonzi DS, Butters TD (2012) Hydrophilic interaction liquid chromatography of anthranilic acid-labelled oligosaccharides with a 4-aminobenzoic acid ethyl ester-labelled dextran hydrolysate internal standard. J Chromatogr A 1233:66–70PubMedCrossRef

Niethamer TK, Yardeni T, Leoyklang P et al (2012) Oral monosaccharide therapies to reverse renal and muscle hyposialylation in a mouse model of GNE myopathy. Mol Genet Metab 107:748–755PubMedCentralPubMedCrossRef

Nishino I (2006) Autophagic vacuolar myopathy. Semin Pediatr Neurol 13:90–95PubMedCrossRef

Nishino I, Noguchi S, Murayama K et al (2002) Distal myopathy with rimmed vacuoles is allelic to hereditary inclusion body myopathy. Neurology 59:1689–1693PubMedCrossRef

Noguchi S, Keira Y, Murayama K et al (2004) Reduction of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase activity and sialylation in distal myopathy with rimmed vacuoles. J Biol Chem 279:11402–11407PubMedCrossRef

Nonaka I, Murakami N, Suzuki Y, Kawai M (1998) Distal myopathy with rimmed vacuoles. Neuromuscul Disord 8:333–337PubMedCrossRef

Nonaka I, Noguchi S, Nishino I (2005) Distal myopathy with rimmed vacuoles and hereditary inclusion body myopathy. Curr Neurol Neurosci Rep 5:61–65PubMedCrossRef

Nonaka I, Sunohara N, Ishiura S, Satoyoshi E (1981) Familial distal myopathy with rimmed vacuole and lamellar (myeloid) body formation. J Neurol Sci 51:141–155PubMedCrossRef

Paccalet T, Coulombe Z, Tremblay JP (2010) Ganglioside GM3 levels are altered in a mouse model of HIBM: GM3 as a cellular marker of the disease. PLoS One 5:e10055PubMedCentralPubMedCrossRef

Ramachandran N, Munteanu I, Wang P et al (2009) VMA21 deficiency causes an autophagic myopathy by compromising V-ATPase activity and lysosomal acidification. Cell 137:235–246PubMedCrossRef

Schauer R (2009) Sialic acids as regulators of molecular and cellular interactions. Curr Opin Struct Biol 19:507–514PubMedCrossRef

Schwarzkopf M, Knobeloch KP, Rohde E et al (2002) Sialylation is essential for early development in mice. Proc Natl Acad Sci U S A 99:5267–5270PubMedCentralPubMedCrossRef

Sparks SE, Ciccone C, Lalor M et al (2005) Use of a cell-free system to determine UDP-N-acetylglucosamine 2-epimerase and N-acetylmannosamine kinase activities in human hereditary inclusion body myopathy. Glycobiology 15:1102–1110PubMedCrossRef

Valles-Ayoub Y, Esfandiarifard S, Sinai P et al (2012) Serum neural cell adhesion molecule is hyposialylated in hereditary inclusion body myopathy. Genet Test Mol Biomarkers 16:313–317PubMedCrossRef

Varki A (1997) Sialic acids as ligands in recognition phenomena. FASEB J 11:248–255PubMed

Varki A (2008) Sialic acids in human health and disease. Trends Mol Med 14:351–360PubMedCentralPubMedCrossRef

Wang Z, Sun Z, Li AV, Yarema KJ (2006) Roles for UDP-GlcNAc 2-epimerase/ManNAc 6-kinase outside of sialic acid biosynthesis: modulation of sialyltransferase and BiP expression, GM3 and GD3 biosynthesis, proliferation, and apoptosis, and ERK1/2 phosphorylation. J Biol Chem 281:27016–27028PubMedCrossRef

Weidemann W, Stelzl U, Lisewski U et al (2006) The collapsin response mediator protein 1 (CRMP-1) and the promyelocytic leukemia zinc finger protein (PLZF) bind to UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE), the key enzyme of sialic acid biosynthesis. FEBS Lett 580:6649–6654PubMedCrossRef

Wennekes T, van den Berg RJ, Boot RG et al (2009) Glycosphingolipids–nature, function, and pharmacological modulation. Angew Chem Int Ed Engl 48:8848–8869PubMedCrossRef

Yardeni T, Choekyi T, Jacobs K et al (2011) Identification, tissue distribution, and molecular modeling of novel human isoforms of the key enzyme in sialic acid synthesis, UDP-GlcNAc 2-epimerase/ManNAc kinase. Biochemistry 50:8914–8925PubMedCentralPubMedCrossRef

Titel: Non-specific accumulation of glycosphingolipids in GNE myopathy
verfasst von: Katherine A. Patzel
Tal Yardeni
Erell Le Poëc-Celic
Petcharat Leoyklang
Heidi Dorward
Dominic S. Alonzi
Nikolay V. Kukushkin
Bixue Xu
Yongmin Zhang
Matthieu Sollogoub
Yves Blériot
William A. Gahl
Marjan Huizing
Terry D. Butters
Publikationsdatum: 01.03.2014
Verlag: Springer Netherlands
Erschienen in: Journal of Inherited Metabolic Disease / Ausgabe 2/2014
Print ISSN: 0141-8955
Elektronische ISSN: 1573-2665
DOI: https://doi.org/10.1007/s10545-013-9655-6

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Non-specific accumulation of glycosphingolipids in GNE myopathy

Abstract

Background

Methods

Results

Conclusion

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