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J. Biol. Chem., Vol. 277, Issue 23, 20386-20398, June 7, 2002

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Kidney Sulfatides in Mouse Models of Inherited Glycosphingolipid Disorders
DETERMINATION BY NANO-ELECTROSPRAY IONIZATION TANDEM MASS SPECTROMETRY^*

Roger Sandhoff^§, Stefan T. Hepbildikler^¶, Richard Jennemann, Rudolf Geyer, Volkmar Gieselmann^**, Richard L. Proia, Herbert Wiegandt, and Hermann-Josef Gröne

From the  Deutsches Krebsforschungszentrum Heidelberg, Abteilung für Zelluläre und Molekulare Pathologie, INF 280, 69120 Heidelberg, Germany, the ^¶ Kekulé-Institut für Organische Chemie und Biochemie, Universität Bonn, Gerhard-Domagk-Str. 1, 53121 Bonn, Germany, the  Biochemisches Institut am Klinikum der Justus-Liebig-Universität Giessen, 35392 Giessen, Germany, the ^** Physiologisch Chemisches Institut, Rheinische Friedrich Wilhelms Universität, 53115 Bonn, Germany, and the  Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892

Sulfatides show structural, and possibly physiological similarities to gangliosides. Kidney dysfunction might be correlated with changes in sulfatides, the major acidic glycosphingolipids in this organ. To elucidate their in vivo metabolic pathway these compounds were analyzed in mice afflicted with inherited glycosphingolipid disorders. The mice under study lacked the genes encoding either -hexosaminidase -subunit (Hexa/), the -hexosaminidase -subunit (Hexb/), both -hexosaminidase  and -subunits (Hexa/ and Hexb/), GD3 synthase (GD3S/), GD3 synthase and GalNAc transferase (GD3S/ and GalNAcT/), GM2 activator protein (Gm2a/), or arylsulfatase A (ASA/). Quantification of the sulfatides, I³SO-GalCer (SM4s), II³SO-LacCer (SM3), II³SO-Gg₃Cer (SM2a), and IV^3, II³-(SO)₂-Gg₄Cer (SB1a), was performed by nano-electrospray tandem mass spectrometry. We conclude for the in vivo situation in mouse kidneys that: 1) a single enzyme (GalNAc transferase) is responsible for the synthesis of SM2a and GM2 from SM3 and GM3, respectively. 2) In analogy to GD1a, SB1a is degraded via SM2a. 3) SM2a is hydrolyzed to SM3 by -hexosaminidase S (Hex S) and Hex A, but not Hex B. Both enzymes are supported by GM2-activator protein. 4) Arylsulfatase A is required to degrade SB1a. It is probably the sole sphingolipid-sulfatase cleaving the galactosyl-3-sulfate bond. In addition, a human Tay-Sachs patient's liver was investigated, which showed accumulation of SM2a along with GM2 storage. The different ceramide compositions of both compounds indicated they were probably derived from different cell types. These data demonstrate that in vivo the sulfatides of the ganglio-series follow the same metabolic pathways as the gangliosides with the replacement of sulfotransferases and sulfatases by sialyltransferases and sialidases. Furthermore, a novel neutral GSL, IV⁶GlcNAc-Gb₄Cer, was found to accumulate only in Hexa/ and Hexb/ mouse kidneys. From this we conclude that Hex S also efficiently cleaves terminal 1-6-linked HexNAc residues from neutral GSLs in vivo.

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