title: Collapsin response mediator protein-2 phosphorylation promotes the reversible retraction of oligodendrocyte processes in response to non-lethal oxidative stress.
abstract: The extension of processes of oligodendrocyte (OLG) and their precursor cells are crucial for migration, axonal contact and myelination. Here we show that a non-lethal oxidative stress induced by 3-nitropropionic acid (3-NP) elicited a rapid shortening of processes (~24%) in primary OLGs and in oligodendroglial cell line (OLN-93) cells (~36%) as compared with vehicle-exposed cells. This was reversible and prevented by antioxidants. Proteomics of OLG lysates with and without 3-NP treatment yielded collapsin response mediator protein 2 (CRMP-2) as a candidate effector molecule. Inhibition of rho kinase was sufficient to prevent process retraction in both OLGs and OLN-93 cells. Oxidative stress increased phosphorylation of CRMP-2 at T555 that was completely prevented by Y27632. Moreover, transfection of OLN-93 cells with the mutant CRMP-2 T555A which cannot be phosphorylated by rho kinase, prevented process shortening induced by 3-NP as compared with wild-type CRMP-2. Our results suggest a role for endogenous reactive oxygen species in a pathway that regulates OLG process extension. The vulnerability of late myelinated neurons in the adult brain and the presence of white matter pathology in human dementias warrant the study of this oligodendroglial pathway in the early stages of neurodegenerative conditions characterized by oxidative stress.
authors.affiliation: Fundación Instituto Leloir-Instituto de Investigaciones Bioquímicas de Buenos Aires, CONICET, Buenos Aires, Argentina.
authors.forename: Agata
authors.initials: A
authors.lastname: Fernández-Gamba
authors.forename: María Celeste
authors.initials: MC
authors.lastname: Leal
authors.forename: Chera L
authors.initials: CL
authors.lastname: Maarouf
authors.forename: Christiane
authors.initials: C
authors.lastname: Richter-Landsberg
authors.forename: Terence
authors.initials: T
authors.lastname: Wu
authors.forename: Laura
authors.initials: L
authors.lastname: Morelli
authors.forename: Alex E
authors.initials: AE
authors.lastname: Roher
authors.forename: Eduardo M
authors.initials: EM
authors.lastname: Castaño
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D015153:Blotting, Western; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009836:Oligodendroglia / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D018384:Oxidative Stress / Q000502:physiology*; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism / Q000633:toxicity; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014162:Transfection
chemical_list: D000975:Antioxidants; D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D017382:Reactive Oxygen Species; C095114:collapsin response mediator protein-2