Gangliosides play pivotal roles in the regulation of complement systems and in the maintenance of integrity in nerve tissues.
Gangliosides are considered to be essential in the maintenance and repair of nervous tissues; however, the mechanisms for neurodegeneration caused by ganglioside defects are unknown. We examined gene expression profiles in double knockout (DKO) mice of GM2/GD2 synthase and GD3 synthase genes and showed that the majority of complement genes and their receptors were up-regulated in cerebellum in DKO mice. Inflammatory reactions were demonstrated in those tissues by measuring up-regulated inflammatory cytokines, indicating the presence of complement activation and inflammation as reported in Alzheimer's disease. Immunoblotting of fractionated membrane extracts by sucrose density gradient revealed that complement-regulatory molecules such as decay-accelerating factor and CD59 were dispersed from glycolipid-enriched microdomain/rafts in DKO cerebellum. Immunohistostaining of these molecules showed disordered membrane localization. These results suggested that dysfunction of complement-regulatory molecules may be due to abnormal glycolipid-enriched microdomain/rafts that triggered complement activation, subsequent inflammation, and neurodegeneration in DKO mice. Generation of the triple KO mice lacking complement activity in addition to the two glycosyltransferases suggested that complement activation is involved in the inflammatory reactions and neurodegeneration caused by the ganglioside deficiency.
Ohmi
Yuhsuke
Y
Department of Biochemistry II, Nagoya University Graduate School of Medicine, Nagoya 466-0065, Japan.
Tajima
Orie
O
Ohkawa
Yuki
Y
Mori
Atsushi
A
Sugiura
Yasuo
Y
Furukawa
Keiko
K
Furukawa
Koichi
K
D000818:Animals; D018958:CD55 Antigens / Q000378:metabolism; D002531:Cerebellum / Q000276:immunology / Q000378:metabolism; D003176:Complement C3 / Q000172:deficiency / Q000235:genetics; D003165:Complement System Proteins / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000096:biosynthesis; D005732:Gangliosides / Q000378:metabolism*; D020869:Gene Expression Profiling; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D021962:Membrane Microdomains / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D017350:N-Acetylgalactosaminyltransferases / Q000172:deficiency / Q000235:genetics; D009410:Nerve Degeneration / Q000209:etiology / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D009417:Nerve Tissue / Q000276:immunology* / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012799:Sialyltransferases / Q000172:deficiency / Q000235:genetics
D018958:CD55 Antigens; D003176:Complement C3; D016207:Cytokines; D005732:Gangliosides; D018836:Inflammation Mediators; D012333:RNA, Messenger; D003165:Complement System Proteins; D017350:N-Acetylgalactosaminyltransferases; C023220:(N-acetylneuraminyl)-galactosylglucosylceramide N-acetylgalactosaminyltransferase; D012799:Sialyltransferases; C043662:alpha-N-acetylneuraminate alpha-2,8-sialyltransferase