Interruption of Ganglioside Synthesis Produces Central Nervous System Degeneration and Altered Axon-glial Interactions

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2005 Feb 16

PMID 15710896

Citations 93

Authors

Tadashi Yamashita

Yun-Ping Wu

Roger Sandhoff

Norbert Werth

Hiroki Mizukami

Jessica M Ellis

Jeffrey L Dupree

Rudolf Geyer

Konrad Sandhoff

Richard L Proia

Affiliations

Soon will be listed here.

Abstract

Gangliosides, which are sialylated glycosphingolipids, are the major class of glycoconjugates on neurons and carry the majority of the sialic acid within the central nervous system (CNS). To determine the role of ganglioside synthesis within the CNS, mice carrying null mutations in two critical ganglioside-specific glycosyltransferase genes, Siat9 (encoding GM3 synthase) and Galgt1 (encoding GM2 synthase), were generated. These double-null mice were unable to synthesize gangliosides of the ganglio-series of glycosphingolipids, which are the major ganglioside class in the CNS. Soon after weaning, viable mice developed a severe neurodegenerative disease that resulted in death. Histopathological examination revealed striking vacuolar pathology in the white matter regions of the CNS with axonal degeneration and perturbed axon-glia interactions. These results indicate that ganglioside synthesis is essential for the development of a stable CNS, possibly by means of the promotion of interactions between axon and glia.

Citing Articles

Tot O, Mrdenovic S, Ivic V, Roncevic R, Milic J, Viljetic B Curr Issues Mol Biol. 2024; 46(8):8376-8394.

PMID: 39194711 PMC: 11352286. DOI: 10.3390/cimb46080494.

Depletion of b-series ganglioside prevents limb length discrepancy after growth plate injury.

Hosokawa Y, Matsuoka M, Sakai Y, Fukuda R, Matsugasaki K, Homan K BMC Musculoskelet Disord. 2024; 25(1):565.

PMID: 39033138 PMC: 11264953. DOI: 10.1186/s12891-024-07704-7.

Profiling Intact Glycosphingolipids with Automated Structural Annotation and Quantitation from Human Samples with Nanoflow Liquid Chromatography Mass Spectrometry.

Schindler R, Oloumi A, Tena J, Alvarez M, Liu Y, Grijaldo S Anal Chem. 2024; 96(15):5951-5959.

PMID: 38563595 PMC: 11024888. DOI: 10.1021/acs.analchem.4c00077.

Lipid Rafts: The Maestros of Normal Brain Development.

Viljetic B, Blazetic S, Labak I, Ivic V, Zjalic M, Heffer M Biomolecules. 2024; 14(3).

PMID: 38540780 PMC: 10967752. DOI: 10.3390/biom14030362.

Neural-specific alterations in glycosphingolipid biosynthesis and cell signaling associated with two human ganglioside GM3 synthase deficiency variants.

Dookwah M, Wagner S, Ishihara M, Yu S, Ulrichs H, Kulik M Hum Mol Genet. 2023; 32(24):3323-3341.

PMID: 37676252 PMC: 10695682. DOI: 10.1093/hmg/ddad146.

References

Yamashita T, Hashiramoto A, Haluzik M, Mizukami H, Beck S, Norton A . Enhanced insulin sensitivity in mice lacking ganglioside GM3. Proc Natl Acad Sci U S A. 2003; 100(6):3445-9. PMC: 152312. DOI: 10.1073/pnas.0635898100. View

Coetzee T, Fujita N, Dupree J, Shi R, Blight A, Suzuki K . Myelination in the absence of galactocerebroside and sulfatide: normal structure with abnormal function and regional instability. Cell. 1996; 86(2):209-19. DOI: 10.1016/s0092-8674(00)80093-8. View

Aicardi J, Castelein P . Infantile neuroaxonal dystrophy. Brain. 1979; 102(4):727-48. DOI: 10.1093/brain/102.4.727. View

Vyas A, Schnaar R . Brain gangliosides: functional ligands for myelin stability and the control of nerve regeneration. Biochimie. 2001; 83(7):677-82. DOI: 10.1016/s0300-9084(01)01308-6. View

Yamashita T, Higuchi H, Tohyama M . The p75 receptor transduces the signal from myelin-associated glycoprotein to Rho. J Cell Biol. 2002; 157(4):565-70. PMC: 2173856. DOI: 10.1083/jcb.200202010. View

Svennerholm L . CHROMATOGRAPHIC SEPARATION OF HUMAN BRAIN GANGLIOSIDES. J Neurochem. 1963; 10:613-23. DOI: 10.1111/j.1471-4159.1963.tb08933.x. View

Kabayama K, Ito N, Honke K, Igarashi Y, Inokuchi J . Suppression of integrin expression and tumorigenicity by sulfation of lactosylceramide in 3LL Lewis lung carcinoma cells. J Biol Chem. 2001; 276(29):26777-83. DOI: 10.1074/jbc.M100428200. View

Svennerholm L, Bostrom K, Fredman P, Mansson J, Rosengren B, Rynmark B . Human brain gangliosides: developmental changes from early fetal stage to advanced age. Biochim Biophys Acta. 1989; 1005(2):109-17. DOI: 10.1016/0005-2760(89)90175-6. View

Inokuchi J, Kabayama K, Uemura S, Igarashi Y . Glycosphingolipids govern gene expression. Glycoconj J. 2004; 20(3):169-78. DOI: 10.1023/B:GLYC.0000024248.62242.1f. View

10.

Okada M, Haraguchi M, Okajima T, Inoue M, Oishi H, Matsuda Y . b-series Ganglioside deficiency exhibits no definite changes in the neurogenesis and the sensitivity to Fas-mediated apoptosis but impairs regeneration of the lesioned hypoglossal nerve. J Biol Chem. 2001; 277(3):1633-6. DOI: 10.1074/jbc.C100395200. View

11.

Yu R, Bieberich E, Xia T, Zeng G . Regulation of ganglioside biosynthesis in the nervous system. J Lipid Res. 2004; 45(5):783-93. DOI: 10.1194/jlr.R300020-JLR200. View

12.

Williams M, McCluer R . The use of Sep-Pak C18 cartridges during the isolation of gangliosides. J Neurochem. 1980; 35(1):266-9. DOI: 10.1111/j.1471-4159.1980.tb12515.x. View

13.

Popko B . Myelin galactolipids: mediators of axon-glial interactions?. Glia. 2000; 29(2):149-53. DOI: 10.1002/(sici)1098-1136(20000115)29:2<149::aid-glia8>3.0.co;2-4. View

14.

Poliak S, Peles E . The local differentiation of myelinated axons at nodes of Ranvier. Nat Rev Neurosci. 2003; 4(12):968-80. DOI: 10.1038/nrn1253. View

15.

COLLINS B, Yang L, Mukhopadhyay G, Filbin M, Kiso M, Hasegawa A . Sialic acid specificity of myelin-associated glycoprotein binding. J Biol Chem. 1997; 272(2):1248-55. DOI: 10.1074/jbc.272.2.1248. View

16.

Vyas A, Patel H, Fromholt S, Heffer-Lauc M, Vyas K, Dang J . Gangliosides are functional nerve cell ligands for myelin-associated glycoprotein (MAG), an inhibitor of nerve regeneration. Proc Natl Acad Sci U S A. 2002; 99(12):8412-7. PMC: 123081. DOI: 10.1073/pnas.072211699. View

17.

Marcus J, Dupree J, Popko B . Myelin-associated glycoprotein and myelin galactolipids stabilize developing axo-glial interactions. J Cell Biol. 2002; 156(3):567-77. PMC: 2173329. DOI: 10.1083/jcb.200111047. View

18.

Honke K, Hirahara Y, Dupree J, Suzuki K, Popko B, Fukushima K . Paranodal junction formation and spermatogenesis require sulfoglycolipids. Proc Natl Acad Sci U S A. 2002; 99(7):4227-32. PMC: 123630. DOI: 10.1073/pnas.032068299. View

19.

Kolter T, Proia R, Sandhoff K . Combinatorial ganglioside biosynthesis. J Biol Chem. 2002; 277(29):25859-62. DOI: 10.1074/jbc.R200001200. View

20.

Takamiya K, Yamamoto A, Yamashiro S, Shin M, Okada M, Fukumoto S . Mice with disrupted GM2/GD2 synthase gene lack complex gangliosides but exhibit only subtle defects in their nervous system. Proc Natl Acad Sci U S A. 1996; 93(20):10662-7. PMC: 38211. DOI: 10.1073/pnas.93.20.10662. View