Gangliosides play pivotal roles in the regulation of complement systems and in the maintenance of integrity in nerve tissues

Abstract

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.cerebellum ͉ degeneration ͉ inflammation ͉ knockout ͉ lipid raft

Complement inhibition decreases the procoagulant response and confers organ protection in a baboon model of Escherichia coli sepsis

“…The direct effects include its ability to induce exposure of procoagulant lipids, 24,25 activate platelets, 26,27 increase TF expression in various cell types, 28 induce the release of microparticles and inhibit fibrinolysis by up-regulation of PAI1. 29 Our data demonstrate that complement inhibition decreases fibrin deposition by regulating both the coagulation and fibrinolytic pathways via TF and PAI-1 expression.…”

Roles of gangliosides in mouse embryogenesis and embryonic stem cell differentiation

“…They are widely found in the plasma membranes of all vertebrate tissues and are particularly abundant in the central nervous system (CNS) (Svennerholm, 1980;Yu et al, 2004). Complement-induced neuron degeneration and the phenotypes of genetically engineered mice lacking gangliosides, i.e., mice with a double knockout in GM2/GD2 synthase and GD3 synthase (Ohmi et al, 2009), clearly demonstrate that gangliosides have a wide variety of functional roles (Proia, 2003). Clinically, GSLs play important roles in the pathogenesis of certain neuropathies such as Guillain-Barré syndrome, a disorder caused by an autoimmune response to cell surface gangliosides (Kaida et al, 2009), and autosomal recessive infantile-onset symptomatic epilepsy syndrome, a disorder caused by a nonsense mutation in GM3 synthase (Simpson et al, 2004).…”

Molecular triggers of neuroinflammation in mouse models of demyelinating diseases

“…Thus, when exposed to abnormal myelin, C1q binding could indicate an altered composition of these ganglioside-rich (sialic acid-containing glycolipids) raft-like microdomains. Indeed, the histopathologic features of neuroinflammation were ameliorated when an additional mutation affecting complement factor synthesis was included (Ohmi et al, 2009). Since peroxisomes are essential for myelin lipid turnover, it would be important to know whether peroxisomal mouse mutants harbor myelin lipid rafts that are altered in composition and associated with C1q-mediated complement factor as a cause of neuroinflammation and demyelination (Figure 2).…”