Abstract
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 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.
Highlights
Gangliosides are a family of sialic acid-containing glycosphingolipids expressed on the external leaflet of most eukaryotic cell plasma membranes and highly enriched in nervous tissue (Yu et al, 2011)
The role of individual gangliosides in neurodegeneration has been interrogated by transgenic manipulations at different stages in the biosynthesis pathway (Yu et al, 2011), but less is known about the contribution of more precise cellular membrane expression on phenotypes
On the Dbl KO background, we reintroduced neuronal expression of the GalNAc-T gene to characterise the importance of a-series ganglioside expression selectively on neuronal membranes
Summary
Gangliosides are a family of sialic acid-containing glycosphingolipids expressed on the external leaflet of most eukaryotic cell plasma membranes and highly enriched in nervous tissue (Yu et al, 2011). In the absence of sulfatide, which is highly expressed on the glial membrane, we have previously shown that a-series gangliosides alone are insufficient to abrogate the lethal phenotype in GD3s−/− × CST−/− mice, suggesting b-series gangliosides are functionally important (McGonigal et al, 2019) To interrogate this further we expressed a-series gangliosides selectively in neurons of GM3-only mice in the absence of b-series gangliosides to explore their critical role in more detail. Whilst reintroduction of a-series gangliosides in neurons largely restored survival and behavioural phenotype of GM3-only mice, this was insufficient to completely attenuate axon degeneration or nodal disruption, suggesting the requirement for glial, and/or b-series ganglioside expression for normal nervous system function and integrity
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