title: Microglia-induced activation of non-canonical Wnt signaling aggravates neurodegeneration in demyelinating disorders.
abstract: Oligodendrocytes are myelinating cells of the central nervous system. Multiple sclerosis (MS) is a demyelinating disease characterized by both myelin loss and neuronal degeneration. However, the molecular mechanisms underlying neuronal degeneration in demyelinating disorders are not fully understood. In the experimental autoimmune encephalomyelitis (EAE) demyelinating mouse model of MS, inflammatory microglia produce cytokines including interleukin-1β (IL-1β). Since microglia and non-canonical Wnt signaling components in neurons, such as the co-receptor Ror2, were observed in the spinal cord of EAE mice, we postulated that the interplay between activated microglia and spinal neurons under EAE conditions is mediated through non-canonical Wnt signaling. EAE treatment up-regulated in vivo expression of non-canonical Wnt signaling components in spinal neurons through microglial activation. In accordance with the neuronal degeneration detected in the EAE spinal cord in vivo, co-culture of spinal neurons with microglia or the application of recombinant IL-1β up-regulated non-canonical Wnt signaling, and induced neuronal cell death, which was suppressed by the inhibition of the Wnt-Ror2 pathway. Ectopic non-canonical Wnt signaling aggravated the demyelinating pathology in another MS mouse model due to Wnt5a-induced neurodegeneration. The linkage between activated microglia and neuronal Wnt-Ror2 signaling may provide a possible candidate target for therapeutic approaches to demyelinating disorders.
authors.affiliation: Division of Neurobiology and Bioinformatics, National Institute for Physiological Sciences, 5-1 Higashiyama Myodaiji Okazaki, Aichi 444-8787, Japan Department of Physiological Sciences, School of Life Sciences, SOKENDAI; (The Graduate University for Advanced Studies), Okazaki 444-8787, Japan shimizu@nips.ac.jp.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Shimizu
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, 's-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands.
authors.forename: Ron
authors.initials: R
authors.lastname: Smits
authors.affiliation: Division of Neurobiology and Bioinformatics, National Institute for Physiological Sciences, 5-1 Higashiyama Myodaiji Okazaki, Aichi 444-8787, Japan Department of Physiological Sciences, School of Life Sciences, SOKENDAI; (The Graduate University for Advanced Studies), Okazaki 444-8787, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Ikenaka