Connexins in neuromyelitis optica: A link between astrocytopathy and demyelination

Chloé Richard, Anne Ruiz, Sylvie Cavagna, Maxime Bigotte, Sandra Vukusic, Katsuhisa Masaki, Toshihiko Suenaga, Jun Ichi Kira, Pascale Giraudon, Romain Marignier

Research output: Contribution to journalArticlepeer-review

14 Citations (Scopus)


Neuromyelitis optica, a rare neuroinflammatory demyelinating disease of the CNS, is characterized by the presence of specific pathogenic autoantibodies directed against the astrocytic water channel aquaporin 4 (AQP4) and is now considered as an astrocytopathy associated either with complement-dependent astrocyte death or with astrocyte dysfunction. However, the link between astrocyte dysfunction and demyelination remains unclear. We propose glial intercellular communication, supported by connexin hemichannels and gap junctions, to be involved in demyelination process in neuromyelitis optica. Using mature myelinated cultures, we demonstrate that a treatment of 1 h to 48 h with immunoglobulins purified from patients with neuromyelitis optica (NMO-IgG) is responsible for a complement independent demyelination, compared to healthy donors' immunoglobulins (P 5 0.001). In parallel, patients' immunoglobulins induce an alteration of connexin expression characterized by a rapid loss of astrocytic connexins at the membrane followed by an increased size of gap junction plaques (+ 60%; P 5 0.01). This was co-observed with connexin dysfunction with gap junction disruption (-57%; P 5 0.001) and increased hemichannel opening (+ 17%; P 5 0.001), associated with glutamate release. Blocking connexin 43 hemichannels with a specific peptide was able to prevent demyelination in co-treatment with patients compared to healthy donors' immunoglobulins. By contrast, the blockade of connexin 43 gap junctions with another peptide was detrimental for myelin (myelin density -48%; P 5 0.001). Overall, our results suggest that dysregulation of connexins would play a pathogenetic role in neuromyelitis optica. The further identification of mechanisms leading to connexin dysfunction and soluble factors implicated, would provide interesting therapeutic strategies for demyelinating disorders.

Original languageEnglish
Pages (from-to)2721-2732
Number of pages12
Issue number9
Publication statusPublished - Sept 1 2020

All Science Journal Classification (ASJC) codes

  • Clinical Neurology


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