title: Dock3 protects myelin in the cuprizone model for demyelination.
abstract: Dedicator of cytokinesis 3 (Dock3) belongs to an atypical family of the guanine nucleotide exchange factors. It is predominantly expressed in the neural tissues and causes cellular morphological changes by activating the small GTPase Rac1. We previously reported that Dock3 overexpression protects retinal ganglion cells from excitotoxic cell death. Oligodendrocytes are the myelinating cells of axons in the central nervous system and these cells are damaged in demyelinating disorders including multiple sclerosis (MS) and optic neuritis. In this study, we examined if Dock3 is expressed in oligodendrocytes and if increasing Dock3 signals can suppress demyelination in a cuprizone-induced demyelination model, an animal model of MS. We demonstrate that Dock3 is expressed in oligodendrocytes and Dock3 overexpression protects myelin in the corpus callosum following cuprizone treatment. Furthermore, we show that cuprizone demyelinates optic nerves and the extent of demyelination is ameliorated in mice overexpressing Dock3. Cuprizone treatment impairs visual function, which was demonstrated by multifocal electroretinograms, an established non-invasive method, and Dock3 overexpression prevented this effect. In mice overexpressing Dock3, Erk activation is increased, suggesting this may at least partly explain the observed protective effects. Our findings suggest that Dock3 may be a therapeutic target for demyelinating disorders including optic neuritis.Cell Death and Disease (2014) 5, e1395; doi:10.1038/cddis.2014.357; published online 28 August 2014.
authors.affiliation: Visual Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Namekata
authors.affiliation: Visual Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Kimura
authors.affiliation: Visual Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: C
authors.initials: C
authors.lastname: Harada
authors.affiliation: Department of Neuro-ophthalmology, Tokyo Metropolitan Neurological Hospital, Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Yoshida
authors.affiliation: Visual Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Matsumoto
authors.affiliation: 1] Visual Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan [2] Department of Neuro-ophthalmology, Tokyo Metropolitan Neurological Hospital, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Harada
mesh_terms: D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D002614:Chelating Agents / Q000633:toxicity; D003337:Corpus Callosum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003471:Cuprizone / Q000633:toxicity; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004596:Electroretinography; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D004676:Myelin Basic Protein / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009836:Oligodendroglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009900:Optic Nerve / Q000378:metabolism / Q000473:pathology; D012160:Retina / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction
chemical_list: D002352:Carrier Proteins; D002614:Chelating Agents; C410623:Dock3 protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D004676:Myelin Basic Protein; D009419:Nerve Tissue Proteins; D003471:Cuprizone; D048049:Extracellular Signal-Regulated MAP Kinases; D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases