Olesoxime favors oligodendrocyte differentiation through a functional interplay between mitochondria and microtubules.
Multiple sclerosis (MS) is a neurodegenerative disease characterized by episodes of immune attacks and oligodendrocyte death leading to demyelination and progressive functional deficits. New therapeutic strategies are needed to stimulate the spontaneous regenerative process observed in some patients. Spontaneous myelin repair relies on the mobilization and differentiation of endogenous oligodendrocyte progenitors at the lesion site. Olesoxime, a cholesterol-like compound, has been shown to favor oligodendrocyte maturation in culture and promote myelin regeneration in rodents. Here, we study the mode of action of this compound and show that it binds to oligodendrocyte mitochondria, leading to their hyperfilamentation. This is accompanied by a reduction of basal superoxide levels, and accumulation of End Binding Protein 1 (EB1) at growing ends of microtubules. In parallel, we demonstrate that Reactive Oxygen Species (ROS) scavengers also promote oligodendrocyte differentiation, together with increasing mitochondrial filamentation and EB1-dependent microtubule polymerization. Altogether, our data uncover the mechanisms by which olesoxime promotes oligodendrocyte maturation. They also reveal that a bidirectional relationship between mitochondria hyperfilamentation and ROS level modulation controls oligodendrocyte maturation. This study identifies new cellular mechanisms to target for the development of regenerative treatments for MS.
Aix Marseille Univ, CNRS, IBDM, Marseille, France.
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K
Magalon
Aix Marseille Univ, INSERM, CRO2, Marseille, France.
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M
Le Grand
Aix Marseille Univ, CNRS, IBDM, Marseille, France.
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B
El Waly
Center of Developmental Biology (CBD), Research Center on Animal Cognition (CRCA), Center for Integrative Biology (CBI), Toulouse University, CNRS, UPS, France.
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M
Moulis
Trophos SA, Parc Scientifique de Luminy, Luminy Biotech Entreprises, Case 931, 13288 Marseille Cedex 9, France.
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R
Pruss
Trophos SA, Parc Scientifique de Luminy, Luminy Biotech Entreprises, Case 931, 13288 Marseille Cedex 9, France.
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T
Bordet
Aix Marseille Univ, CNRS, IBDM, Marseille, France.
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M
Cayre
Center of Developmental Biology (CBD), Research Center on Animal Cognition (CRCA), Center for Integrative Biology (CBI), Toulouse University, CNRS, UPS, France.
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P
Belenguer
Aix Marseille Univ, INSERM, CRO2, Marseille, France.
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M
Carré
Aix Marseille Univ, CNRS, IBDM, Marseille, France. Electronic address: pascale.durbec@univ-amu.fr.
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Durbec
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D002783:Cholestenones / Q000494:pharmacology* / Q000627:therapeutic use; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009103:Multiple Sclerosis / Q000378:metabolism / Q000517:prevention & control; D004676:Myelin Basic Protein / Q000378:metabolism; D019579:Neocortex / Q000187:drug effects / Q000378:metabolism; D009836:Oligodendroglia / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism
D002783:Cholestenones; C561584:Mapre1 protein, rat; D008869:Microtubule-Associated Proteins; D004676:Myelin Basic Protein; D017382:Reactive Oxygen Species; D013481:Superoxides; C522838:olesoxime
Cell differentiation; Mdivi-1 (PubChem CID: 3825829); Microtubule dynamics; MitoTEMPO (PubChem CID: 54613387); Mitochondria; Olesoxime; Olesoxime (PubChem CID: 21763506); Oligodendrocyte; Paclitaxel (PubChem CID: 36314); Tiron (PubChem CID: 9001)