Regulatory mechanisms of nervous systems with glycosphingolipids

A number of studies have suggested functions of sialic acid-containing glycosphingolipids (gangliosides) in the nervous system. However, results of analyses of the mutant mice lacking gangliosides suggested that they play crucial roles in the maintenance of integrity and repair of the nervous tissues. Furthermore, results of double knockout mice lacking all gangliosides except GM3 (GM3-only mice) suggested that deficiency of gangliosides induced complement activation and inflammation, leading to neurodegeneration. Generation of triple knockout mice by mating GM3-only mice and C3-deficient mice verified the involvement of complement systems in the inflammation and neurodegeneration. For the mechanisms of the complement activation, functional disorders of complement-regulatory proteins such as CD55 and CD59, which belong to GPI-anchored proteins, should be main factors. These results suggested that normal composition of gangliosides is essential for the maintenance of lipid rafts. Therefore, it was suggested that regulation of the complement systems and suppression of the inflammation should be important for the treatment of neurodegeneration, having common aspects with other neurodegenerative diseases such as Alzheimer disease.