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EMBO Mol Med. 2019 Nov 7;11(11):e10378. doi: 10.15252/emmm.201910378. Epub 2019 Sep 30.

Disruption of Sema3A/Plexin-A1 inhibitory signalling in oligodendrocytes as a therapeutic strategy to promote remyelination.

Author information

1
INSERM U1119 Biopathology of Myelin, Neuroprotection, Therapeutic Strategy, Labex Medalis, Fédération de Médecine Translationnelle de Strasbourg, Strasbourg University, Strasbourg, France.
2
Institut de Physique Biologique, Faculté de Médecine, Strasbourg University, Strasbourg, France.

Abstract

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.

KEYWORDS:

Plexin; Semaphorin; multiple sclerosis; myelination; oligodendrocyte

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