The role of gangliosides in the organisation of the node of Ranvier examined in glycosyltransferase transgenic mice

Abstract

Gangliosides are sialic acid containing glycosphingolipids widely expressed in vertebrate plasma membranes and intracellular compartments (Ledeen & Wu, 2011;Sandhoff & Harzer, 2013;Yu et al., 2011). Whilst ganglioside biosynthesis and distribution is widespread throughout the body, the nervous system in particular is very highly enriched in complex gangliosides relative to other organs and tissues. Gangliosides are present in both central and peripheral nervous system (CNS and PNS) grey and white matter, where they have roles in development and homeostasis, modulating cell-cell recognition, signal transduction, growth and motility. Gangliosides are key components of lipid raft membrane domains where they have been widely studied (Simons & Toomre, 2000;Sonnino et al., 2015). In this review, we will focus our attention on the role of gangliosides in the maintenance of the mammalian node of Ranvier (NoR), a specialised membrane domain formed by myelin-forming cells: Schwann cells in the PNS and oligodendrocytes in the CNS (Figure 1). The NoR is a critical relay station in the electrophysiological functioning of myelinating nerve fibres, essential for saltatory conduction, promoted by high density clustering of voltage-gated sodium (Nav) channels on the nodal axolemma.Anchoring of the myelin paranodal loops by adhesion molecules and their associated cytoskeletal linker proteins in both the glial and axonal membranes at the paranode segregate and condense the ion channels (Pinatel & Faivre-Sarrailh, 2021;Rasband & Peles, 2021). Of note to our review, disruption to the expression of the paranodal axo-glial membrane protein complex composed of glial Neurofascin 155 (NF155), axonal contactin-associated

Schwann cell nodal membrane disruption triggers bystander axonal degeneration in a Guillain-Barré syndrome mouse model

“…In order to exclusively target axonal or glial membranes via anti-GM1 antibody–mediated injury, we developed transgenic mouse strains that have complex ganglioside expression limited to neurons (and thus also their axon projections) through the human Thy1.2 promoter [ GalNAc-T –/– -Tg(neuronal) , Neuronal ] or myelinating and non-myelinating glia through the mouse proteolipid protein ( Plp ) promoter [ GalNAc-T –/– -Tg(glial) , Glial ] ( Figure 1A ), as previously reported ( 12 , 20 , 21 ). Firstly, we used triangularis sterni (TS) nerve–muscle preparations to study the differing binding patterns of a single monoclonal anti-GM1 antibody (DG2) ( 22 ) at distal nerves and NoRs from Neuronal and Glial mice compared to wild-type (WT) mice ( Figure 1, B and C ).…”

“…Additionally, mice were crossed with B6.Cg-Tg mice that endogenously express cytosolic cyan fluorescent protein (CFP) in their axons ( 21 ). Mice from the GalNAc-T –/– -Tg(neuronal) or GalNAc-T –/– -Tg(glial) background exhibit age-dependent neurodegeneration ( 20 ); therefore, we elected to use 4- to 6-week-old mice, both male and female, that have no identifiable phenotype ( 12 ). The number of mice per treatment are reported per experiment.…”

“…Briefly, GalNAc-T −/− -Tg(neuronal) mice express the full-length cDNA encoding GalNAc-T under the control of the human Thy1.2 promoter (restricted to mature neurons), and GalNAc-T −/− -Tg(glial) mice express the full-length cDNA encoding GalNAc-T under the control of the mouse PLP promoter (restricted to glia, including myelinating and non-myelinating Schwann cells). Mice from the GalNAc-T −/− -Tg(neuronal) or GalNAc-T −/− -Tg(glial) background exhibit agedependent neurodegeneration (20), therefore we elected to use 4-6 week old mice, both male and female, that have no identifiable phenotype (12). The number of mice per treatment are reported per experiment.…”

“…Gangliosides are highly enriched in nervous system plasma membranes relative to other tissues ( 11 ). GM1 is expressed on both axolemmal and SC membranes and is particularly exposed at NoRs and motor nerve terminals (MNTs) ( 12 ), sites essential for saltatory conduction and synaptic transmission, respectively. The development of transgenic mice null for β4-GalNAc transferase that synthesizes complex gangliosides has demonstrated their essential role in the stability and function of the NoR ( 13 ).…”

Editorial: Peripheral nerve anatomy in health and disease

“…Mutations in ganglioside biosynthesis genes cause complex neurodevelopmental and neurodegenerative disorders (Sandhoff & Harzer, 2013), while gangliosides themselves can act as receptors for autoantibodies, including those that cause the severe acute paralytic neuropathy GBS (Willison et al, 2016). In the final article of the Collection, McGonigal & Willison review the importance of gangliosides in the formation and organisation of the mammalian node of Ranvier, the specialised axonal domain found between myelin‐forming cells that enables saltatory conduction (McGonigal & Willison, 2022). After describing the network of gangliosides and other glycolipids at the node, the ramifications of widespread and tissue‐specific ganglioside deficiencies in transgenic mice are examined, both in relation to ganglioside function and to the study of autoimmune‐driven injury at the node of Ranvier.…”