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Review
. 2020 Mar 11;21(6):1906.
doi: 10.3390/ijms21061906.

Novel Molecular Mechanisms of Gangliosides in the Nervous System Elucidated by Genetic Engineering

Koichi Furukawa  1   2 , Yuhsuke Ohmi  3 , Farhana Yesmin  1   2 , Orie Tajima  1 , Yuji Kondo  2 , Pu Zhang  1   2 , Noboru Hashimoto  4 , Yuki Ohkawa  5 , Robiul H Bhuiyan  1 , Keiko Furukawa  1
Affiliations
Review

Novel Molecular Mechanisms of Gangliosides in the Nervous System Elucidated by Genetic Engineering

Koichi Furukawa et al. Int J Mol Sci. .

Abstract

Acidic glycosphingolipids, i.e., gangliosides, are predominantly and consistently expressed in nervous tissues of vertebrates at high levels. Therefore, they are considered to be involved in the development and function of nervous systems. Recent studies involving genetic engineering of glycosyltransferase genes have revealed novel aspects of the roles of gangliosides in the regulation of nervous tissues. In this review, novel findings regarding ganglioside functions and their modes of action elucidated mainly by studies of gene knockout mice are summarized. In particular, the roles of gangliosides in the regulation of lipid rafts to maintain the integrity of nervous systems are reported with a focus on the roles in the regulation of neuro-inflammation and neurodegeneration via complement systems. In addition, recent advances in studies of congenital neurological disorders due to genetic mutations of ganglioside synthase genes and also in the techniques for the analysis of ganglioside functions are introduced.

Keywords: ganglioside; glycosphingolipid; inflammation; knockout; microdomain; neurodegeneration.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Glycosphingolipids are amphipathic molecules, expressed in the out layer of lipid two layers of the cell membrane. The hydrophobic portion (ceramide) is embedded in the outer layer of the membrane, and the sugar portion is protruding outside the membrane. A representative GM1 structure is shown. Ganglioside nomenclature is according to Svennerholm [10].
Figure 2
Figure 2
Main pathway of ganglioside synthesis. Glycosyltransferases catalyzing individual steps are shown by italics, and deleted structures in KO mice are shown by different colored squares. Structures on the line of ganglioside synthesis are presented in green letters.
Figure 3
Figure 3
Immunohistochemistry of GFAP-positive astrocytes and F4/80-positive microglia. Cerebella from 50-week-old mice were analyzed by anti-glial fibrillary acidic protein (GFAP) antibody and Alexa Fluor 555-conjugated anti-mouse IgG1, and anti-mouse F4/80 and Alexa Fluor 488-conjugated anti-rat IgG. Marked gliosis was found in ganglioside synthase gene KO mice. GFAP-positive cells were increased (upper, red), and F4/80-positive cells (lower, green) accumulated in cerebella, indicating astrocytes and microglia, respectively. Scale bar, 50 µm in both panels. Borders between layers of the cerebellum indicated based on Hematoxylin-Eosin staining of serial sections.
Figure 4
Figure 4
Inflammatory reactions in DKO mice were suppressed by genetic disruption of complement system. (A) Triple KO (TKO) mice were generated by mating DKO mice with C3 KO mice to clarify the roles of complement systems in brain disorders in DKO mice. (B) Expression levels of inflammatory cytokines were reduced in TKO mice. Relative mRNA levels of TNFα and IL-1β were compared using RT-qPCR.
Figure 5
Figure 5
Destruction of the GEM/raft induced changes in the architecture and functions of raft-localizing molecules. Localization of GPI-anchored proteins including complement-regulatory molecules changed, leading to functional abnormalities and subsequent complement activation and inflammation in ganglioside-deficient mouse brain. GPI-anchored molecules such as DAF and NCAM as well as GEM/raft markers shifted from GEM/rafts to non-rafts domains. A part of a figure in Ref. 81 was presented after modification. Among isoforms of NCAM, only the GPI-anchored one was detected in GEM/rafts.
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References

    1. Batool S., Hussain Raza H., Zaidi J., Riaz S., Hasan S., Syed N.I. Synapse Formation: From Cellular and Molecular Mechanisms to Neurodevelopmental and Neurodegenerative Disorders. J. Neurophysiol. 2019;121:1381–1397. doi: 10.1152/jn.00833.2018. - DOI - PubMed
    1. Ando S. Neuronal dysfunction with aging and its amelioration. Proc. Jpn. Acad. Ser. B Phys. Biol. Sci. 2012;88:266–282. doi: 10.2183/pjab.88.266. - DOI - PMC - PubMed
    1. Moll T., Shaw P.J., Cooper-Knock J. Disrupted glycosylation of lipids and proteins is a cause of neurodegeneration. Brain. 2019 doi: 10.1093/brain/awz358. - DOI - PMC - PubMed
    1. Yu R.K., Tsai Y.T., Ariga T. Functional roles of gangliosides in neurodevelopment: An overview of recent advances. Neurochem. Res. 2012;37:1230–1244. doi: 10.1007/s11064-012-0744-y. - DOI - PMC - PubMed
    1. Itokazu Y., Wang J., Yu R.K. Gangliosides in nerve cell specification. Prog. Mol. Biol. Transl. Sci. 2018;156:241–263. - PMC - PubMed

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