Myelin-Associated Glycoprotein (MAG) Protects Neurons from Acute Toxicity Using a Ganglioside-Dependent Mechanism

Abstract

Myelin-associated glycoprotein (MAG), a protein expressed on the innermost wrap of myelin, contributes to long-term axon stability as evidenced by progressive axon degeneration in Mag-null mice. Recently, MAG was also found to protect axons from acute toxic insults. In the current study, rat dorsal root ganglion neurons were cultured on control substrata and substrata adsorbed with myelin proteins. Neurons on myelin-adsorbed surfaces were resistant to acute degeneration of neurites induced by vincristine, a cancer chemotherapeutic agent with neuropathic side effects. Myelin-mediated protection was reversed by anti-MAG antibody and was absent when cells were cultured on extracts from Mag-null mouse myelin, confirming the protective role of MAG. Gangliosides (sialylated glycosphingolipids) are one functional class of axonal receptors for MAG. In the current studies, a direct role for gangliosides in mediating the acute protective effects of MAG was established. Treatment of neurons with sialidase, an enzyme that cleaves the terminal sialic acids required for MAG binding, reversed MAG's protective effect, as did treatment with (1R,2R)-1-phenyl-2-hexadecanoylamino-3-pyrrolidino-1-propanol, an inhibitor of glycosphingolipid biosynthesis. In contrast, treatment with phosphatidylinositol-specific phospholipase C, an enzyme that cleaves Nogo receptors (NgR, another class of MAG receptor), or with a peptide inhibitor of an NgR-associated signaling molecule p75NTR, failed to diminish MAG-mediated protection. Inhibiting the Rho-associated protein kinase ROCK reversed protection. We conclude that MAG protects neurites from acute toxic insult via a ganglioside-mediated signaling pathway that involves activation of RhoA. Understanding MAG-mediated protection may provide opportunities to reduce axonal damage and loss.

Probing the importance of lipid diversity in cell membranes via molecular simulation

“…Membrane models of other mammalian organs are currently ripe for MD simulations, such as peripheral myelin sheath (PMS) membranes. These membranes contain glycolipids such as GalCer that constitute 10% of lipids in the PMS (Svennerholm et al, 1992) and more complex gangliosides that are important to membrane function (Mehta et al, 2010;Svennerholm et al, 1994). These glycolipids also exist in many different biological membranes (Róg, 2014), but the quantity and quality of simulations with gylcolipids have been limited and this area is ripe for further study and potential force field development.…”

Erythropoietin promotes axonal regeneration after optic nerve crush in vivo by inhibition of RhoA/ROCK signaling pathway

“…ROCK activation enhances phosphorylation of myosin light-chain phosphatase, which is a key regulator in cytoskeletal rearrangement (Brown and Bridgman, 2004). ROCK inhibitor Y-27632 can inhibit the activity of ROCK-1 and ROCK-2 (Ishizaki et al, 1996;Mehta et al, 2010) and promote axon growth (Lingor et al, 2008;Watanabe, 2010). It has been shown that crosstalk exists between hypoxia inducible factor-1 (HIF-1) and ROCK pathways in neuronal differentiation of mesenchymal stem cells, neurospheres and in PC12 neurite outgrowth (Pacary et al, 2007), and EPO is one of the major target genes of HIF-1, therefore, EPO and RhoA/ROCK pathway may also participate in the crosstalk.…”

Ganglioside GM1 induces phosphorylation of mutant huntingtin and restores normal motor behavior in Huntington disease mice

“…By influencing membrane properties and/or by direct interaction with membrane proteins, gangliosides modulate the activity of many tyrosine kinase (25-28) and neurotransmitter receptors (29), ion channels (30, 31), and downstream cell signaling pathways. In addition, gangliosides regulate axon-myelin communication and the maintenance of myelinated axons in the adult central and peripheral nervous systems (32)(33)(34).Consistent with the pivotal role of gangliosides in the nervous system and in cell signaling, defects in their biosynthetic pathway lead to a severe infantile neurodegenerative disorder characterized by progressive brain atrophy, chorea, and epilepsy (35), symptoms that are also common to the juvenile form of HD (36).We hypothesized that in HD, decreased GM1 levels contribute to neuronal dysfunction and disease pathogenesis. Supporting this hypothesis, we demonstrated that restoring normal GM1 levels in an HD neural cell line stimulates the activation of prosurvival cell signaling pathways and provides protection from apoptosis.…”

“…By influencing membrane properties and/or by direct interaction with membrane proteins, gangliosides modulate the activity of many tyrosine kinase (25)(26)(27)(28) and neurotransmitter receptors (29), ion channels (30,31), and downstream cell signaling pathways. In addition, gangliosides regulate axon-myelin communication and the maintenance of myelinated axons in the adult central and peripheral nervous systems (32)(33)(34).…”