Neuronally expressed a-series gangliosides are sufficient to prevent the lethal age-dependent phenotype in GM3-only expressing mice

McGonigal, R. , Barrie, J. A., Yao, D., Black, L. E. , McLaughlin, M. and Willison, H. J. (2021) Neuronally expressed a-series gangliosides are sufficient to prevent the lethal age-dependent phenotype in GM3-only expressing mice. Journal of Neurochemistry, 158(2), pp. 217-232. (doi: 10.1111/jnc.15365) (PMID:33864399)

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Gangliosides are expressed on plasma membranes throughout the body and enriched in the nervous system. A critical role for complex a‐ and b‐series gangliosides in central and peripheral nervous system ageing has been established through transgenic manipulation of enzymes in ganglioside biosynthesis. Disrupting GalNAc‐transferase (GalNAc‐T), thus eliminating all a‐ and b‐series complex gangliosides (with consequent over‐expression of GM3 and GD3) leads to an age‐dependent neurodegeneration. Mice that express only GM3 ganglioside (double knockout produced by crossing GalNAc‐T‐/‐ and GD3 synthase‐/‐ mice, Dbl KO) display markedly accelerated neurodegeneration with reduced survival. Degenerating axons and disrupted to the node of Ranvier architecture are key features of complex ganglioside‐deficient mice. Previously, we have shown that reintroduction of both a‐ and b‐series gangliosides into neurons on a global GalNAcT ‐/‐ background is sufficient to rescue this age‐dependent neurodegenerative phenotype. To determine the relative roles of a‐ and b‐series gangliosides in this rescue paradigm, we herein reintroduced GalNAc‐T into neurons of Dbl KO mice, thereby reconstituting a‐series but not b‐series complex gangliosides. We assessed survival, axon degeneration, axo‐glial integrity, inflammatory markers, and lipid‐raft formation in these Rescue mice compared to wild type and Dbl KO mice. We found that this neuronal reconstitution of a‐series complex gangliosides abrogated the adult lethal phenotype in Dbl KO mice, and partially attenuated the neurodegenerative features. This suggests that whilst neuronal expression of a‐series gangliosides is critical for survival during ageing, it is not entirely sufficient to restore complete nervous system integrity in the absence of either b‐series or glial a‐series gangliosides.

Item Type:Articles
Glasgow Author(s) Enlighten ID:McLaughlin, Dr Mark and McGonigal, Dr Rhona and Barrie, Mrs Jennifer and Willison, Professor Hugh and Yao, Dr Denggao and Black, Ms Lauren
Authors: McGonigal, R., Barrie, J. A., Yao, D., Black, L. E., McLaughlin, M., and Willison, H. J.
College/School:College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
Research Centre:College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Immunobiology
Journal Name:Journal of Neurochemistry
ISSN (Online):1471-4159
Published Online:17 April 2021
Copyright Holders:Copyright © 2021 International Society for Neurochemistry
First Published:First published in Journal of Neurochemistry 158(2): 217-232
Publisher Policy:Reproduced under a Creative Commons License

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