title: MiR-146a promotes remyelination in a cuprizone model of demyelinating injury.
abstract: The death of mature oligodendrocytes (OLs) which are the sole myelinating cells of the central nervous system (CNS), leads to demyelination and functional deficits. Currently, there is lack of effective remyelination therapies for patients with demyelinating diseases. MicroRNAs (miRNAs) mediate OL function. We hypothesized that miR-146a, by inactivating interleukin-1 receptor-associated kinase 1 (IRAK1), promotes differentiation of oligodendrocyte progenitor cells (OPCs) and thereby enhances remyelination. To test this hypothesis, a demyelination model induced by a cuprizone (CPZ) diet was employed, in which C57BL/6J mice were fed with a CPZ diet for 5weeks. After termination of CPZ diet, the mice were randomly treated with continuous infusion of miR-146a mimics or mimic controls into the corpus callosum for 7days. Compared to the mimic control, infusion of miR-146a mimics facilitated remyelination assessed by increased myelin basic proteins in the corpus callosum, which was associated with augmentation of newly generated mature OLs. Infusion of miR-146a mimics also substantially elevated miR-146a levels in the corpus callosum and fluorescently tagged miR-146a mimics were mainly detected in OPCs. Western blot and double immmunofluorescent staining analysis showed that the miR-146a treatment considerably reduced IRAK1 protein levels and the number of IRAK1-positive cells, respectively. Collectively, these data indicate that exogenous miR-146a enhances remyelination, possibly by promoting OPCs to differentiate into myelinated OLs via targeting IRAK1.
authors.affiliation: Department of Neurology, Henry Ford Health System, Detroit, MI 48202, United States. Electronic address: jingz@neuro.hfh.edu.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Neurology, Henry Ford Health System, Detroit, MI 48202, United States.
authors.forename: Zheng Gang
authors.initials: ZG
authors.lastname: Zhang
authors.affiliation: Biostatistics and Research Epidemiology, Henry Ford Health System, Detroit, MI 48202, United States.
authors.forename: Mei
authors.initials: M
authors.lastname: Lu
authors.affiliation: Department of Neurology, Henry Ford Health System, Detroit, MI 48202, United States.
authors.forename: Xinli
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Neurology, Henry Ford Health System, Detroit, MI 48202, United States.
authors.forename: Xia
authors.initials: X
authors.lastname: Shang
authors.affiliation: Department of Neurology, Henry Ford Health System, Detroit, MI 48202, United States.
authors.forename: Stanton B
authors.initials: SB
authors.lastname: Elias
authors.affiliation: Department of Neurology, Henry Ford Health System, Detroit, MI 48202, United States; Department of Physics, Oakland University, Rochester, MI 48309, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Chopp
mesh_terms: D000818:Animals; D003337:Corpus Callosum / Q000187:drug effects* / Q000378:metabolism; D003471:Cuprizone; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000494:pharmacology / Q000627:therapeutic use*; D055495:Neurogenesis / Q000187:drug effects*; D009836:Oligodendroglia / Q000187:drug effects
chemical_list: D035683:MicroRNAs; C534190:Mirn146 microRNA, mouse; D003471:Cuprizone
keywords: IRAK1; cuprizone; miR-146a; oligodendrocyte; oligodendrocyte progenitor cells; remyelination