The Experts below are selected from a list of 7524 Experts worldwide ranked by ideXlab platform
Y Zhang - One of the best experts on this subject based on the ideXlab platform.
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Synthetic sulfoGalactosylceramide (sulfatide) and its use for the mass spectrometric quantitative urinary determination in metachromatic leukodystrophies.
Glycoconjugate Journal, 2008Co-Authors: Y. Curi,, Nancy Baumann, B. Colsh,, Carlos Afonso, Jean-claude Tabet, Jean-maurice Mallet, Y ZhangAbstract:3-O-SulfoGalactosylceramides (sulfatides) accumulate in the genetic disease metachromatic leukodystrophy which is due to a defect in the catabolic enzyme, arylsulfatase A. Clinical diagnosis is usually confirmed by in vitro enzymatic deficiency of arylsulfatase A activity. The diagnosis may be complicated because of arylsulfatase A pseudo-deficiencies and another cause of MLD, sphingolipid activator B deficiency. As large quantities of sulfatides can be found in the urine in this disease, sulfatiduria appears as an extremely useful test. As recently enzyme replacement is underway, the quantitative determination, using an internal standard, appears particularly useful as a follow-up. Thus a non-physiological sulfatide was synthesized for this purpose, i.e. 3-O-sulfo-beta-D-C17 Galactosylceramide (3-O-Sulfo-D: -Galactosyl-beta1'-->1-N-Heptadecanoyl-D-erythro-Sphingosine). It has been prepared through condensation of an azidosphingosine derivative with a protected D-galactopyranosyltrichloroacetimidate. Reduction of the azide was followed by acylation of a C-17 fatty acid. The key step was achieved by selective sulfation of the desired hydroxyl group on the sugar residue of the Galactosylceramide using the stannylene methodology to give a 3'-sulfated beta-galactosyl C-17 ceramide.
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synthetic sulfoGalactosylceramide sulfatide and its use for the mass spectrometric quantitative urinary determination in metachromatic leukodystrophies
Glycoconjugate Journal, 2008Co-Authors: Benoit Colsch, Nancy Baumann, Carlos Afonso, Jean-claude Tabet, Jean-maurice Mallet, Y ZhangAbstract:3-O-SulfoGalactosylceramides (sulfatides) accumulate in the genetic disease metachromatic leukodystrophy which is due to a defect in the catabolic enzyme, arylsulfatase A. Clinical diagnosis is usually confirmed by in vitro enzymatic deficiency of arylsulfatase A activity. The diagnosis may be complicated because of arylsulfatase A pseudo-deficiencies and another cause of MLD, sphingolipid activator B deficiency. As large quantities of sulfatides can be found in the urine in this disease, sulfatiduria appears as an extremely useful test. As recently enzyme replacement is underway, the quantitative determination, using an internal standard, appears particularly useful as a follow-up. Thus a non-physiological sulfatide was synthesized for this purpose, i.e. 3-O-sulfo-β-d-C17 Galactosylceramide (3-O-Sulfo-d-Galactosyl-β1′→1-N-Heptadecanoyl-d-erythro-Sphingosine). It has been prepared through condensation of an azidosphingosine derivative with a protected d-galactopyranosyltrichloroacetimidate. Reduction of the azide was followed by acylation of a C-17 fatty acid. The key step was achieved by selective sulfation of the desired hydroxyl group on the sugar residue of the Galactosylceramide using the stannylene methodology to give a 3′-sulfated beta-galactosyl C-17 ceramide.
Janeric Mansson - One of the best experts on this subject based on the ideXlab platform.
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Distribution of cholesterol and Galactosylceramide in rat cerebellar white matter.
Biochimica et biophysica acta, 2006Co-Authors: Katrin Borner, Hakan Nygren, Birgit Hagenhoff, Per Malmberg, Elke Tallarek, Janeric ManssonAbstract:White matter and the inner granular layer of rat cerebellum was analysed by imaging time-of-flight secondary-ion mass spectrometry (TOF-SIMS) equipped with a Bi+ ion cluster gun. Samples were prepared by high pressure freezing, freeze-fracturing and freeze drying or by plunge freezing and cryostat sectioning. The identified and localized chemical species were: sodium, potassium, phosphocholine, cholesterol and Galactosylceramide (GalC) with carbon chain lengths C18:0 (N-stearoyl-Galactosylceramide) and C24:0 (N-lignoceroylGalactosylceramide) with CH24:0 (hydroxy-lignoceroylGalactosylceramide). We report new findings regarding the organization of myelin in white matter. One is cholesterol-rich, ribbon-shaped 10-20 microm areas excluding Na+ and K+. The second finding is the different distribution of GalC C18 and GalC C24 in relation to these areas, where GalC C18 was localized in cholesterol-rich areas and GalC C24 was localized in Na/K-enriched areas. The distribution of GalC was in small spots, homogeneous in size, of 0.8-1.5 microm. Sample preparation with high pressure freezing allowed separate localization of sodium and potassium in tissue samples.
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localization of cholesterol phosphocholine and Galactosylceramide in rat cerebellar cortex with imaging tof sims equipped with a bismuth cluster ion source
Biochimica et Biophysica Acta, 2005Co-Authors: Hakan Nygren, Katrin Borner, Birgit Hagenhoff, Per Malmberg, Janeric ManssonAbstract:Time-of-flight secondary-ion-mass-spectrometry (TOF-SIMS) was utilized to address the issue of co-localization of cholesterol, phosphocholine and Galactosylceramide in rat cerebellar cortex. Rat cerebellum was fixed, freeze-protected by sucrose, frozen and sectioned by cryoultramicrotomy and dried at room temperature. The samples were analyzed in an imaging TOF-SIMS instrument equipped with a Bi(1-7)+-source. The cholesterol signal (m/z 369 and 385) was localized in Purkinje cells and in nuclei of granular layer cells. The phosphocholine headgroup of phosphatidylcholine and sphingomyelin was localized by imaging a specific fragment (m/z 86). This signal was localized in the molecular layer of cerebellar cortex, in Purkinje cells and in parts of the granular layer probably representing the synapse-rich glomeruli. The Galactosylceramide was localized by imaging the quasi-molecular ions at m/z 835 and 851, showed a clear colocalization with cholesterol, but also a specific localization in dots (diameter
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Localization of cholesterol, phosphocholine and Galactosylceramide in rat cerebellar cortex with imaging TOF-SIMS equipped with a bismuth cluster ion source.
Biochimica et biophysica acta, 2005Co-Authors: Hakan Nygren, Katrin Borner, Birgit Hagenhoff, Per Malmberg, Janeric ManssonAbstract:Time-of-flight secondary-ion-mass-spectrometry (TOF-SIMS) was utilized to address the issue of co-localization of cholesterol, phosphocholine and Galactosylceramide in rat cerebellar cortex. Rat cerebellum was fixed, freeze-protected by sucrose, frozen and sectioned by cryoultramicrotomy and dried at room temperature. The samples were analyzed in an imaging TOF-SIMS instrument equipped with a Bi(1-7)+-source. The cholesterol signal (m/z 369 and 385) was localized in Purkinje cells and in nuclei of granular layer cells. The phosphocholine headgroup of phosphatidylcholine and sphingomyelin was localized by imaging a specific fragment (m/z 86). This signal was localized in the molecular layer of cerebellar cortex, in Purkinje cells and in parts of the granular layer probably representing the synapse-rich glomeruli. The Galactosylceramide was localized by imaging the quasi-molecular ions at m/z 835 and 851, showed a clear colocalization with cholesterol, but also a specific localization in dots (diameter
Kinuko Suzuki - One of the best experts on this subject based on the ideXlab platform.
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Twitcher mice with only a single active Galactosylceramide synthase gene exhibit clearly detectable but therapeutically minor phenotypic improvements.
Journal of neuroscience research, 2000Co-Authors: Takanori Ezoe, Brian Popko, Kinuko Suzuki, Marie T. Vanier, Yasushi Oya, Jun Tohyama, Junko Matsuda, Kunihiko SuzukiAbstract:Cross-breeding of mouse mutants, each defective in either synthesis (CGT knockout) or degradation (twitcher) of Galactosylceramide, generates hybrids with a genotype of galc-/-, cgt+/-, in addition to doubly deficient mice. They are ideally suited to test the potential usefulness of limiting synthesis of the substrate as a treatment of genetic disorders due to degradative enzyme defects. The rate of accretion of Galactosylceramide in the brain of CGT knockout carrier mice (cgt+/-) is approximately two-thirds of the normal, suggesting a gene-level compensation for the reduced gene dosage. Phenotype of twitcher mice with a single dose of normal cgt gene was indeed milder with statistical significance, albeit only slightly. Compared among 10 paired littermates, the difference in the life span was 7 ± 3.9 days (S.D.) and the difference in the maximum attained body weight was 1.9 ± 1.2 g (S.D.). Neuropathologists were able to distinguish blindly galc-/-, cgt+/- mice from galc-/-, cgt+/+ mice. The brain psychosine level in galc-/-, cgt+/- mice was also approximately two-thirds of the galc-/-, cgt+/+ mice. These observations indicate that reduction of Galactosylceramide synthesis to two-thirds of the normal level results in minor but clearly detectable phenotypic improvements. Because of the detrimental consequences of drastic reduction in Galactosylceramide synthesis that may be required for pragmatically meaningful improvements, this approach by itself is unlikely to be useful as the sole treatment but may be helpful as a supplement to other therapies. J. Neurosci. Res. 59:179–187, 2000 © 2000 Wiley-Liss, Inc.
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Biochemistry and neuropathology of mice doubly deficient in synthesis and degradation of Galactosylceramide
Journal of neuroscience research, 2000Co-Authors: Takanori Ezoe, Brian Popko, Kinuko Suzuki, Marie T. Vanier, Yasushi Oya, Jun Tohyama, Junko Matsuda, Kunihiko SuzukiAbstract:We have generated mice doubly deficient in both synthesis and degradation of Galactosylceramide by cross-breeding twitcher mice and Galactosylceramide synthase (UDP-galactose:ceramide galactosyltransferase, CGT) knockout mice. The prediction that the phenotype of the doubly deficient mice should be the same as the cgt -/- mice, since the degrading enzyme should not be necessary if the substrate is not synthesized, proved to be only partially correct. In early stages of the disease, the doubly deficient mice (galc -/-, cgt -/-) were essentially indistinguishable from the cgt -/- mice. However, the doubly deficient mice had a much shorter life span than cgt -/- mice. Both Galactosylceramide and galactosylsphingosine (psychosine), were undetectable in the brain of the cgt -/- and the doubly deficient mice. The characteristic twitcher pathology was never seen in the galc -/-, cgt -/- mice. However, after 43 days, neuronal pathology was observed in the brainstem and spinal cord. This late neuronal pathology has not been seen in the CGT knockout mice but has been described in some long surviving bone marrow-transplanted twitcher mice. Furthermore, the motor segment of the trigeminal nerve of the galc -/-, cgt -/- mice showed severe degeneration not seen in either twitcher or CGT knockout mice. Thus, the galc -/-, cgt -/- mice, while primarily showing the cgt -/- phenotype as predicted, develop late pathology that is seen only in twitcher mouse and also a unique pathology in the trigeminal nerve. These observations indicate that the functional relationship between galactosylceramidase and Galactosylceramide synthase is complex.
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Suppressed UDP-galactose: ceramide galactosyltransferase and myelin protein mRNA in twitcher mouse brain.
Journal of Neuroscience Research, 1998Co-Authors: Masako Taniike, Kunihiko Suzuki, Jill Marcus, Toshinori Nishigaki, Nobuya Fujita, Brian Popko, Kinuko SuzukiAbstract:The developmental changes in expression of steady-state mRNA that encode proteins that are important for myelination (myelin basic protein, myelin-associated glycoprotein, proteolipid protein, UDP-galactose: ceramide galactosyltransferase) and glial fibrillary acidic protein were investigated in the brain of the twitcher mouse, a model of human globoid cell leukodystrophy. This disease is caused by a mutation in the gene encoding the lysosomal enzyme, galactosylceramidase, which catalyzes the degradation of the myelin lipid Galactosylceramide. Before postnatal day (PND) 20, the levels of myelin protein mRNA were similar in twitcher and normal mice. With progression of demyelination after PND 25-30, myelin protein mRNA levels gradually decreased. The period of maximum expression of the myelin protein genes in twitcher mice was, however, similar to that of normal control mice. mRNA levels for the gene that encodes the enzyme UDP-galactose:ceramide galactosyltransferase which is responsible for catalyzing the final step in Galactosylceramide synthesis, was exceptionally down-regulated from the early stages of the disease. The increase of glial fibrillary acidic protein (GFAP) mRNA levels preceded morphological evidence of demyelination.
Kunihiko Suzuki - One of the best experts on this subject based on the ideXlab platform.
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Biochemistry and neuropathology of mice doubly deficient in synthesis and degradation of Galactosylceramide
Journal of neuroscience research, 2000Co-Authors: Takanori Ezoe, Brian Popko, Kinuko Suzuki, Marie T. Vanier, Yasushi Oya, Jun Tohyama, Junko Matsuda, Kunihiko SuzukiAbstract:We have generated mice doubly deficient in both synthesis and degradation of Galactosylceramide by cross-breeding twitcher mice and Galactosylceramide synthase (UDP-galactose:ceramide galactosyltransferase, CGT) knockout mice. The prediction that the phenotype of the doubly deficient mice should be the same as the cgt -/- mice, since the degrading enzyme should not be necessary if the substrate is not synthesized, proved to be only partially correct. In early stages of the disease, the doubly deficient mice (galc -/-, cgt -/-) were essentially indistinguishable from the cgt -/- mice. However, the doubly deficient mice had a much shorter life span than cgt -/- mice. Both Galactosylceramide and galactosylsphingosine (psychosine), were undetectable in the brain of the cgt -/- and the doubly deficient mice. The characteristic twitcher pathology was never seen in the galc -/-, cgt -/- mice. However, after 43 days, neuronal pathology was observed in the brainstem and spinal cord. This late neuronal pathology has not been seen in the CGT knockout mice but has been described in some long surviving bone marrow-transplanted twitcher mice. Furthermore, the motor segment of the trigeminal nerve of the galc -/-, cgt -/- mice showed severe degeneration not seen in either twitcher or CGT knockout mice. Thus, the galc -/-, cgt -/- mice, while primarily showing the cgt -/- phenotype as predicted, develop late pathology that is seen only in twitcher mouse and also a unique pathology in the trigeminal nerve. These observations indicate that the functional relationship between galactosylceramidase and Galactosylceramide synthase is complex.
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Twitcher mice with only a single active Galactosylceramide synthase gene exhibit clearly detectable but therapeutically minor phenotypic improvements.
Journal of neuroscience research, 2000Co-Authors: Takanori Ezoe, Brian Popko, Kinuko Suzuki, Marie T. Vanier, Yasushi Oya, Jun Tohyama, Junko Matsuda, Kunihiko SuzukiAbstract:Cross-breeding of mouse mutants, each defective in either synthesis (CGT knockout) or degradation (twitcher) of Galactosylceramide, generates hybrids with a genotype of galc-/-, cgt+/-, in addition to doubly deficient mice. They are ideally suited to test the potential usefulness of limiting synthesis of the substrate as a treatment of genetic disorders due to degradative enzyme defects. The rate of accretion of Galactosylceramide in the brain of CGT knockout carrier mice (cgt+/-) is approximately two-thirds of the normal, suggesting a gene-level compensation for the reduced gene dosage. Phenotype of twitcher mice with a single dose of normal cgt gene was indeed milder with statistical significance, albeit only slightly. Compared among 10 paired littermates, the difference in the life span was 7 ± 3.9 days (S.D.) and the difference in the maximum attained body weight was 1.9 ± 1.2 g (S.D.). Neuropathologists were able to distinguish blindly galc-/-, cgt+/- mice from galc-/-, cgt+/+ mice. The brain psychosine level in galc-/-, cgt+/- mice was also approximately two-thirds of the galc-/-, cgt+/+ mice. These observations indicate that reduction of Galactosylceramide synthesis to two-thirds of the normal level results in minor but clearly detectable phenotypic improvements. Because of the detrimental consequences of drastic reduction in Galactosylceramide synthesis that may be required for pragmatically meaningful improvements, this approach by itself is unlikely to be useful as the sole treatment but may be helpful as a supplement to other therapies. J. Neurosci. Res. 59:179–187, 2000 © 2000 Wiley-Liss, Inc.
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Drastically abnormal gluco- and Galactosylceramide composition does not affect ganglioside metabolism in the brain of mice deficient in Galactosylceramide synthase.
Neurochemical research, 1999Co-Authors: Kunihiko Suzuki, Marie T. Vanier, Timothy Coetzee, Brian PopkoAbstract:Mice that are genetically deficient in UDP-galactose: ceramide galactosyltransferase are unable to synthesize Galactosylceramide. Consequently, sulfatide, which can be synthesized only by sulfation of Galactosylceramide, is also totally absent in affected mouse brain. α-Hydroxy fatty acid-containing glucosylceramide partially replaces the missing Galactosylceramide. A substantial proportion of sphingomyelin, which normally contains only non-hydroxy fatty acids, also contains α-hydroxy fatty acids. These findings indicate that α-hydroxy fatty acid-containing ceramide normally present only in Galactosylceramide and sulfatide is diverted to other compounds because they cannot be synthesized into Galactosylceramide due to the lack of the galactosyltransferase. We have examined brain gangliosides in order to determine if α-hydroxy fatty acid-containing glucosylceramide present in an abnormally high concentration is also incorporated into gangliosides. The brain ganglioside composition, however, is entirely normal in both the total amount and molecular distribution in these mice. One feasible explanation is that UDP-galactose: glucosylceramide galactosyltransferase does not recognize α-hydroxy fatty acid-containing glucosylceramide as acceptor. This analytical finding is consistent with the relative sparing of gray matter in the affected mice and provides an insight into sphingolipid metabolism in the mouse brain.
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Suppressed UDP-galactose: ceramide galactosyltransferase and myelin protein mRNA in twitcher mouse brain.
Journal of Neuroscience Research, 1998Co-Authors: Masako Taniike, Kunihiko Suzuki, Jill Marcus, Toshinori Nishigaki, Nobuya Fujita, Brian Popko, Kinuko SuzukiAbstract:The developmental changes in expression of steady-state mRNA that encode proteins that are important for myelination (myelin basic protein, myelin-associated glycoprotein, proteolipid protein, UDP-galactose: ceramide galactosyltransferase) and glial fibrillary acidic protein were investigated in the brain of the twitcher mouse, a model of human globoid cell leukodystrophy. This disease is caused by a mutation in the gene encoding the lysosomal enzyme, galactosylceramidase, which catalyzes the degradation of the myelin lipid Galactosylceramide. Before postnatal day (PND) 20, the levels of myelin protein mRNA were similar in twitcher and normal mice. With progression of demyelination after PND 25-30, myelin protein mRNA levels gradually decreased. The period of maximum expression of the myelin protein genes in twitcher mice was, however, similar to that of normal control mice. mRNA levels for the gene that encodes the enzyme UDP-galactose:ceramide galactosyltransferase which is responsible for catalyzing the final step in Galactosylceramide synthesis, was exceptionally down-regulated from the early stages of the disease. The increase of glial fibrillary acidic protein (GFAP) mRNA levels preceded morphological evidence of demyelination.
Brian Popko - One of the best experts on this subject based on the ideXlab platform.
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Biochemistry and neuropathology of mice doubly deficient in synthesis and degradation of Galactosylceramide
Journal of neuroscience research, 2000Co-Authors: Takanori Ezoe, Brian Popko, Kinuko Suzuki, Marie T. Vanier, Yasushi Oya, Jun Tohyama, Junko Matsuda, Kunihiko SuzukiAbstract:We have generated mice doubly deficient in both synthesis and degradation of Galactosylceramide by cross-breeding twitcher mice and Galactosylceramide synthase (UDP-galactose:ceramide galactosyltransferase, CGT) knockout mice. The prediction that the phenotype of the doubly deficient mice should be the same as the cgt -/- mice, since the degrading enzyme should not be necessary if the substrate is not synthesized, proved to be only partially correct. In early stages of the disease, the doubly deficient mice (galc -/-, cgt -/-) were essentially indistinguishable from the cgt -/- mice. However, the doubly deficient mice had a much shorter life span than cgt -/- mice. Both Galactosylceramide and galactosylsphingosine (psychosine), were undetectable in the brain of the cgt -/- and the doubly deficient mice. The characteristic twitcher pathology was never seen in the galc -/-, cgt -/- mice. However, after 43 days, neuronal pathology was observed in the brainstem and spinal cord. This late neuronal pathology has not been seen in the CGT knockout mice but has been described in some long surviving bone marrow-transplanted twitcher mice. Furthermore, the motor segment of the trigeminal nerve of the galc -/-, cgt -/- mice showed severe degeneration not seen in either twitcher or CGT knockout mice. Thus, the galc -/-, cgt -/- mice, while primarily showing the cgt -/- phenotype as predicted, develop late pathology that is seen only in twitcher mouse and also a unique pathology in the trigeminal nerve. These observations indicate that the functional relationship between galactosylceramidase and Galactosylceramide synthase is complex.
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Twitcher mice with only a single active Galactosylceramide synthase gene exhibit clearly detectable but therapeutically minor phenotypic improvements.
Journal of neuroscience research, 2000Co-Authors: Takanori Ezoe, Brian Popko, Kinuko Suzuki, Marie T. Vanier, Yasushi Oya, Jun Tohyama, Junko Matsuda, Kunihiko SuzukiAbstract:Cross-breeding of mouse mutants, each defective in either synthesis (CGT knockout) or degradation (twitcher) of Galactosylceramide, generates hybrids with a genotype of galc-/-, cgt+/-, in addition to doubly deficient mice. They are ideally suited to test the potential usefulness of limiting synthesis of the substrate as a treatment of genetic disorders due to degradative enzyme defects. The rate of accretion of Galactosylceramide in the brain of CGT knockout carrier mice (cgt+/-) is approximately two-thirds of the normal, suggesting a gene-level compensation for the reduced gene dosage. Phenotype of twitcher mice with a single dose of normal cgt gene was indeed milder with statistical significance, albeit only slightly. Compared among 10 paired littermates, the difference in the life span was 7 ± 3.9 days (S.D.) and the difference in the maximum attained body weight was 1.9 ± 1.2 g (S.D.). Neuropathologists were able to distinguish blindly galc-/-, cgt+/- mice from galc-/-, cgt+/+ mice. The brain psychosine level in galc-/-, cgt+/- mice was also approximately two-thirds of the galc-/-, cgt+/+ mice. These observations indicate that reduction of Galactosylceramide synthesis to two-thirds of the normal level results in minor but clearly detectable phenotypic improvements. Because of the detrimental consequences of drastic reduction in Galactosylceramide synthesis that may be required for pragmatically meaningful improvements, this approach by itself is unlikely to be useful as the sole treatment but may be helpful as a supplement to other therapies. J. Neurosci. Res. 59:179–187, 2000 © 2000 Wiley-Liss, Inc.
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Drastically abnormal gluco- and Galactosylceramide composition does not affect ganglioside metabolism in the brain of mice deficient in Galactosylceramide synthase.
Neurochemical research, 1999Co-Authors: Kunihiko Suzuki, Marie T. Vanier, Timothy Coetzee, Brian PopkoAbstract:Mice that are genetically deficient in UDP-galactose: ceramide galactosyltransferase are unable to synthesize Galactosylceramide. Consequently, sulfatide, which can be synthesized only by sulfation of Galactosylceramide, is also totally absent in affected mouse brain. α-Hydroxy fatty acid-containing glucosylceramide partially replaces the missing Galactosylceramide. A substantial proportion of sphingomyelin, which normally contains only non-hydroxy fatty acids, also contains α-hydroxy fatty acids. These findings indicate that α-hydroxy fatty acid-containing ceramide normally present only in Galactosylceramide and sulfatide is diverted to other compounds because they cannot be synthesized into Galactosylceramide due to the lack of the galactosyltransferase. We have examined brain gangliosides in order to determine if α-hydroxy fatty acid-containing glucosylceramide present in an abnormally high concentration is also incorporated into gangliosides. The brain ganglioside composition, however, is entirely normal in both the total amount and molecular distribution in these mice. One feasible explanation is that UDP-galactose: glucosylceramide galactosyltransferase does not recognize α-hydroxy fatty acid-containing glucosylceramide as acceptor. This analytical finding is consistent with the relative sparing of gray matter in the affected mice and provides an insight into sphingolipid metabolism in the mouse brain.
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Suppressed UDP-galactose: ceramide galactosyltransferase and myelin protein mRNA in twitcher mouse brain.
Journal of Neuroscience Research, 1998Co-Authors: Masako Taniike, Kunihiko Suzuki, Jill Marcus, Toshinori Nishigaki, Nobuya Fujita, Brian Popko, Kinuko SuzukiAbstract:The developmental changes in expression of steady-state mRNA that encode proteins that are important for myelination (myelin basic protein, myelin-associated glycoprotein, proteolipid protein, UDP-galactose: ceramide galactosyltransferase) and glial fibrillary acidic protein were investigated in the brain of the twitcher mouse, a model of human globoid cell leukodystrophy. This disease is caused by a mutation in the gene encoding the lysosomal enzyme, galactosylceramidase, which catalyzes the degradation of the myelin lipid Galactosylceramide. Before postnatal day (PND) 20, the levels of myelin protein mRNA were similar in twitcher and normal mice. With progression of demyelination after PND 25-30, myelin protein mRNA levels gradually decreased. The period of maximum expression of the myelin protein genes in twitcher mice was, however, similar to that of normal control mice. mRNA levels for the gene that encodes the enzyme UDP-galactose:ceramide galactosyltransferase which is responsible for catalyzing the final step in Galactosylceramide synthesis, was exceptionally down-regulated from the early stages of the disease. The increase of glial fibrillary acidic protein (GFAP) mRNA levels preceded morphological evidence of demyelination.
