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

• Published in: EMBO molecular medicine 2019-11, Vol.11 (11), p.e10378-n/a
• Main Authors: Binamé, Fabien, Pham‐Van, Lucas D, Spenlé, Caroline, Jolivel, Valérie, Birmpili, Dafni, Meyer, Lionel A, Jacob, Laurent, Meyer, Laurence, Mensah‐Nyagan, Ayikoé G, Po, Chrystelle, Van der Heyden, Michaël, Roussel, Guy, Bagnard, Dominique
• Format: Article
• Language: English
• Subjects: Animals; Brain; Brain - diagnostic imaging; Cell adhesion & migration; Cell Line; Cell Movement; Cell Proliferation; Cuprizone; Demyelination; Disease; Disease Models, Animal; EMBO08; EMBO27; Encephalitis; Experimental allergic encephalomyelitis; Experiments; Life Sciences; Magnetic Resonance Imaging; Mice, Inbred C57BL; Multiple sclerosis; Multiple Sclerosis - physiopathology; Myelin; Myelination; Nerve Tissue Proteins - antagonists & inhibitors; Nerve Tissue Proteins - metabolism; Nervous system; Neurobiology; Neurons and Cognition; oligodendrocyte; Oligodendrocytes; Oligodendroglia - physiology; Peptides; Pharmaceutical sciences; Pharmacology; Plexin; Receptors, Cell Surface - antagonists & inhibitors; Receptors, Cell Surface - metabolism; Remyelination; Semaphorin; Semaphorin-3A - metabolism; Semaphorins; Signal Transduction; Studies
• ISSN: 1757-4676; 1757-4684
• DOI: 10.15252/emmm.201910378

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. Synopsis Sema3A is a repulsive guidance molecule known to impact the migration of several cell types including oligodendrocytes and their progenitors (OPC). In the context of multiple sclerosis (MS), Sema3A is creating a molecular barrier that prevents OPC from entering lesion sites thereby precluding remyelination. The Sema3A receptor Plexin‐A1 is overexpressed in MS patients and is upregulated in animal models of MS. Silencing of Plexin‐A1 in vitro cancels Sema3A inhibitory effects on oligodendrocytes migration and differentiation. The Plexin‐A1 transmembrane domain targeting inhibitory peptide efficiently blocks Sema3A‐induced effects without side effect in vivo . The chronic administration of the peptide in two different mouse models of MS induced beneficial therapeutic effects exemplified by improved myelin content and functional locomotor recovery. Graphical Abstract Sema3A is a repulsive guidance molecule known to impact the migration of several cell types including oligodendrocytes and their progenitors (OPC). In the context of multiple sclerosis (MS), Sema3A is creating a molecular barrier that prevents OPC from entering lesion sites thereby precluding remyelination.