logo amu logo cnrs

UMR 7286 - Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille

Plates-formes PFRN

Accueil > Bibliographie > Specific Contactin N-glycans are implicated in Neurofascin binding and (...)

Specific Contactin N-glycans are implicated in (...)

J Biol Chem. 2014 Mar ;289(11):7907-18
Specific Contactin N-glycans are implicated in Neurofascin binding and autoimmune targeting in peripheral neuropathies.
Labasque M, Hivert B, Nogales-Gadea G, Querol L, Illa I, Faivre-Sarrailh C.

Cell adhesion molecules (CAMs) play a crucial role in the formation of the nodes of Ranvier and in the rapid propagation of the nerve impulses along myelinated axons. These CAMs are the targets of autoimmunity in inflammatory neuropathies. We recently showed that a subgroup of patients with aggressive chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) shows autoantibodies to Contactin (1). The complex of Contactin/Caspr/Neurofascin-155 (NF155) enables the formation of paranodal junctions suggesting that antibody attack against paranodes may participate in the severity of CIDP. In the present study, we mapped the molecular determinants of Contactin targeted by the autoantibodies. In three patients, immunoreactivity was directed against the Ig domains of Contactin and was dependent on N-glycans. The serum of one patient was selectively directed against Contactin bearing mannose-rich N-glycans. Strikingly, the oligomannose type sugars of Contactin are required for association with its glial partner NF155 (2). To investigate precisely the role of Contactin N-glycans, we have mutated each of the 9 consensus N-glycosylation sites independently. We found that the mutation of 3 sites (N467,473,494Q) in the Ig domain 5 of Contactin prevented soluble NF155-Fc binding. In contrast, these mutations did not abolish cis-association with Caspr. Next, we showed that the cluster of N-glycosylation sites (N467, N473, N494) was required for immunoreactivity in one patient. Using cell aggregation assays, we showed that the IgG from the four CIDP patients prevented adhesive interaction between Contactin/Caspr and NF155. Importantly, we showed the anti-Contactin autoantibodies induced alteration of paranodal junctions in myelinated neuronal culture. These results strongly support that antibodies to CAMs may be pathogenic and induce demyelination via functional blocking activity.

PubMed

Le CRN2M en chiffres

  • 20 Chercheurs
  • 19 Enseignants Chercheurs
  • 39 ITAs et IATOs
  • 3 Post-Docs
  • 4 Docs
  • 4 Étudiants de Master

    Ils nous font confiance

  • logo amu
  • logo cnrs
  • logo inserm
  • logo AP-HM
  • logo Galderma
  • logo Ipsem
  • logo Novartis
  • logo Pfizer
  • logo Fédération pour la Recherche sur le Cerveau
  • logo Fondation pour la Recherche Medical en France
  • logo IBiSA
  • logo Europe programme FEDER
  • logo Agence Nationale de la Recherche