Mice lacking complex gangliosides develop Wallerian degeneration and myelination defects

Abstract

Gangliosides are a family of sialic acidcontaining glycosphingolipids highly enriched in the mammalian nervous system. Although they are the major sialoglycoconjugates in the brain, their neurobiological functions remain poorly defined. By disrupting the gene for a key enzyme in complex ganglioside biosynthesis (GM2͞GD2 synthase; EC 2.4.1.92) we generated mice that express only simple gangliosides (GM3͞GD3) and examined their central and peripheral nervous systems. The complex ganglioside knockout mice display decreased central myelination, axonal degeneration in both the central and peripheral nervous systems, and demyelination in peripheral nerves. The pathological features of their nervous system closely resemble those reported in mice with a disrupted gene for myelin-associated glycoprotein (MAG), a myelin receptor that binds to complex brain gangliosides in vitro. Furthermore, GM2͞GD2 synthase knockout mice have reduced MAG expression in the central nervous system. These results indicate that complex gangliosides function in central myelination and maintaining the integrity of axons and myelin. They also support the theory that complex gangliosides are endogenous ligands for MAG. The data extend and clarify prior observations on a similar mouse model, which reported only subtle conduction defects in their nervous system

Alterations in neuroblastoma ganglioside synthesis by induction of GD1b synthase by retinoic acid

“…Secondly, increased expression of GD1b and GT1b in murine NB cells transfected with GD3 synthase occurs in parallel with morphological signs of increased cellular differentiation (Kojima et al, 1994). Thirdly, absence of all gangliosides downstream of GM2/ GD2 synthase (CbG þ GD2 and CaG þ GM2) in genetically altered mice with a disrupted gene for that enzyme is associated with decreased myelination and axon degeneration in the central and peripheral nervous system (Sheikh et al, 1999), although brain development and gross behaviour is normal (Takamiya et al, 1996). Finally, although retinoic acid-induced neurite outgrowth is unaffected by abrogation of cellular ganglioside synthesis in LAN-5 cells grown in a serum-supplemented environment (Li and Ladisch, 1997), reduction of cellular ganglioside synthesis is associated with decreased NGF-induced outgrowth of neuritic processes in a NB cell line grown in serum-free medium, and is reversible by exogenous addition of gangliosides (Rosner, 1998).…”

Neuromuscular synaptic transmission in aged ganglioside-deficient mice

“…Gangliosides seem to become increasingly important upon ageing, as late-onset and progressive histological and behavioural abnormalities develop in both GM2/GD2-synthase knockout (GM2s-KO) mice and compound null-mutant mice lacking GM2/GD2-and GD3-synthase. Young GM2s-KO mice (~3 months) show no phenotype (although they have histological signs of peripheral nerve degeneration (Sheikh et al, 1999), worsening upon ageing ). Eventually, starting at 8-16 months of age, these mice develop motor deficits, i.e.…”

Neuromuscular synaptic function in mice lacking major subsets of gangliosides

“…1; Takamiya et al, 1996;Sheikh et al, 1999) and develop sensory and motor coordination defects upon aging (Chiavegatto et al, 2000;Sugiura et al, 2005). Previously we investigated synaptic transmission in young GM2s-KO mice at NMJs ex vivo (Bullens et al, 2002).…”