title: Anti-ganglioside antibody-mediated activation of RhoA induces inhibition of neurite outgrowth.
abstract: Anti-ganglioside antibodies (Abs) are strongly associated with axonal forms of Guillain Barré syndrome (GBS). Some studies indicate that these Abs, including those with GD1a reactivity, are associated with poor prognosis and/or incomplete recovery. We recently demonstrated that a disease-relevant anti-ganglioside Ab with GD1a reactivity inhibits axon regeneration after PNS injury in an animal model (Lehmann et al., 2007). An implication of these findings is that anti-GD1a Abs can mediate inhibition of axon regeneration and limit recovery in some patients with GBS. The downstream inhibitory intracellular signaling that mediates anti-ganglioside Ab-induced axon inhibition remains unclear. In the current study, we show that disease-relevant and GBS patient's anti-ganglioside Abs can inhibit neurite outgrowth in dissociated primary neuronal cultures. Activation of small GTPase RhoA and its key downstream effector Rho kinase (ROCK) are critical mediators of growth cone and neurite outgrowth inhibition. Therefore, we examined the role of these intracellular signaling molecules in our primary neuronal cultures by molecular and pharmacologic approaches. Our results show that the Ab-mediated inhibition of neurite outgrowth involves the activation of RhoA and ROCK pathway and this activation is through the engagement of specific cell-surface gangliosides by Abs. In summary, these studies directly link patient autoantibodies to an intracellular inhibitory signaling pathway involved in anti-ganglioside Ab-mediated inhibition of neurite outgrowth.
authors.affiliation: Department of Neurology, University of Texas Medical School at Houston, Houston, Texas 77030, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Zhang
authors.forename: Helmar C
authors.initials: HC
authors.lastname: Lehmann
authors.forename: Sowmia
authors.initials: S
authors.lastname: Manoharan
authors.forename: Mohammedali
authors.initials: M
authors.lastname: Hashmi
authors.forename: Sangwoo
authors.initials: S
authors.lastname: Shim
authors.forename: Guo-Li
authors.initials: GL
authors.lastname: Ming
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Schnaar
authors.forename: Pablo H
authors.initials: PH
authors.lastname: Lopez
authors.forename: Nataliia
authors.initials: N
authors.lastname: Bogdanova
authors.forename: Kazim A
authors.initials: KA
authors.lastname: Sheikh
mesh_terms: D000818:Animals; D000906:Antibodies / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005727:Ganglia, Spinal / Q000166:cytology; D005732:Gangliosides / Q000276:immunology*; D020439:Growth Cones / Q000473:pathology; D020275:Guillain-Barre Syndrome / Q000235:genetics / Q000276:immunology / Q000473:pathology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D016501:Neurites / Q000473:pathology*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012583:Schwann Cells / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D014162:Transfection; D020741:rho GTP-Binding Proteins / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein
chemical_list: D000906:Antibodies; D005732:Gangliosides; D054460:rho-Associated Kinases; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein