Disruption of Sema3A/Plexin-A1 inhibitory signalling in oligodendrocytes as a therapeutic strategy to promote remyelination.
Fiche publication
Date publication
septembre 2019
Journal
EMBO molecular medicine
Auteurs
Membres identifiés du Cancéropôle Est :
Dr BAGNARD Dominique, Dr PO Chrystelle
Tous les auteurs :
Binamé F, Pham-Van LD, Spenlé C, Jolivel V, Birmpili D, Meyer LA, Jacob L, Meyer L, Mensah-Nyagan AG, Po C, Van der Heyden M, Roussel G, Bagnard D
Lien Pubmed
Résumé
Current treatments in multiple sclerosis (MS) are modulating the inflammatory component of the disease, but no drugs are currently available to repair lesions. Our study identifies in MS patients the overexpression of Plexin-A1, the signalling receptor of the oligodendrocyte inhibitor Semaphorin 3A. Using a novel type of peptidic antagonist, we showed the possibility to counteract the Sema3A inhibitory effect on oligodendrocyte migration and differentiation in vitro when antagonizing Plexin-A1. The use of this compound in vivo demonstrated a myelin protective effect as shown with DTI-MRI and confirmed at the histological level in the mouse cuprizone model of induced demyelination/remyelination. This effect correlated with locomotor performances fully preserved in chronically treated animals. The administration of the peptide also showed protective effects, leading to a reduced severity of demyelination in the context of experimental autoimmune encephalitis (EAE). Hence, the disruption of the inhibitory microenvironmental molecular barriers allows normal myelinating cells to exert their spontaneous remyelinating capacity. This opens unprecedented therapeutic opportunity for patients suffering a disease for which no curative options are yet available.
Mots clés
Plexin, Semaphorin, multiple sclerosis, myelination, oligodendrocyte
Référence
EMBO Mol Med. 2019 Sep 30;:e10378