title: Induction of paranodal myelin detachment and sodium channel loss in vivo by Campylobacter jejuni DNA-binding protein from starved cells (C-Dps) in myelinated nerve fibers.
abstract: In an axonal variant of Guillain-Barré syndrome (GBS) associated with Campylobacter jejuni (C. jejuni) enteritis, the mechanism underlying axonal damage is obscure. We purified and characterized a DNA-binding protein from starved cells derived from C. jejuni (C-Dps). This C-Dps protein has significant homology with Helicobacter pylori neutrophil-activating protein (HP-NAP), which is chemotactic for human neutrophils through binding to sulfatide. Because sulfatide is essential for paranodal junction formation and for the maintenance of ion channels on myelinated axons, we examined the in vivo effects of C-Dps. First, we found that C-Dps specifically binds to sulfatide by ELISA and immunostaining of thin-layer chromatograms loaded with various glycolipids. Double immunostaining of peripheral nerves exposed to C-Dps with anti-sulfatide antibody and anti-C-Dps antibody revealed co-localization of them. When C-Dps was injected into rat sciatic nerves, it densely bound to the outermost parts of the myelin sheath and nodes of Ranvier. Injection of C-Dps rapidly induced paranodal myelin detachment and axonal degeneration; this was not seen following injection of PBS or heat-denatured C-Dps. Electron microscopically, C-Dps-injected nerves showed vesiculation of the myelin sheath at the nodes of Ranvier. Nerve conduction studies disclosed a significant reduction in compound muscle action potential amplitudes in C-Dps-injected nerves compared with pre-injection values, but not in PBS-, heat-denatured C-Dps-, or BSA-injected nerves. However, C-Dps did not directly affect Na(+) currents in dissociated hippocampal neurons. Finally, when C-Dps was intrathecally infused into rats, it was deposited in a scattered pattern in the cauda equina, especially in the outer part of the myelin sheath and the nodal region. In C-Dps-infused rats, but not in BSA-infused ones, a decrease in the number of sodium channels, vesiculation of the myelin sheath, axonal degeneration and infiltration of Iba-1-positive macrophages were observed. Thus, we consider that C-Dps damages myelinated nerve fibers, possibly through interference with paranodal sulfatide function, and may contribute to the axonal pathology seen in C. jejuni-related GBS.
authors.affiliation: Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Hua
authors.initials: H
authors.lastname: Piao
authors.forename: Motozumi
authors.initials: M
authors.lastname: Minohara
authors.forename: Nobutoshi
authors.initials: N
authors.lastname: Kawamura
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Yoshimitsu
authors.initials: Y
authors.lastname: Mizunoe
authors.forename: Fujio
authors.initials: F
authors.lastname: Umehara
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Goto
authors.forename: Susumu
authors.initials: S
authors.lastname: Kusunoki
authors.forename: Takuya
authors.initials: T
authors.lastname: Matsushita
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Ikenaka
authors.forename: Takashi
authors.initials: T
authors.lastname: Maejima
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Nabekura
authors.forename: Ryo
authors.initials: R
authors.lastname: Yamasaki
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Kira
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001369:Axons / Q000187:drug effects; D016123:Campylobacter jejuni / Q000737:chemistry / Q000378:metabolism*; D002855:Chromatography, Thin Layer; D004268:DNA-Binding Proteins / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D005732:Gangliosides / Q000378:metabolism; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D008854:Microscopy, Electron; D009186:Myelin Sheath / Q000187:drug effects* / Q000473:pathology; D009410:Nerve Degeneration / Q000139:chemically induced / Q000473:pathology; D009413:Nerve Fibers, Myelinated / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D009431:Neural Conduction / Q000187:drug effects; D018408:Patch-Clamp Techniques; D010525:Peripheral Nerves / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D011994:Recombinant Proteins / Q000494:pharmacology; D012584:Sciatic Nerve / Q000187:drug effects / Q000473:pathology; D015222:Sodium Channels / Q000187:drug effects* / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D004268:DNA-Binding Proteins; D005732:Gangliosides; D011994:Recombinant Proteins; D015222:Sodium Channels