title: Gap junction pathology in multiple sclerosis lesions and normal-appearing white matter.
abstract: Oligodendrocyte gap junctions (GJs) are vital for central nervous system myelination, but their involvement in multiple sclerosis (MS) pathology remains unknown. The aim of this study was to examine alterations of oligodendrocyte and related astrocyte GJs in MS lesions and normal-appearing white matter (NAWM). Post-mortem brain samples from 9 MS and 11 age-matched non-MS control patients were studied. Tissue sections that included both chronic active and inactive lesions were characterized neuropathologically with Luxol Fast Blue staining and immunostaining for myelin oligodendrocyte glycoprotein (MOG) and the microglial marker Iba1. We analyzed the expression of Cx32 and Cx47 in oligodendrocytes and of Cx43, the major astrocytic partner in oligodendrocyte-astrocyte (O/A) GJs by quantitative immunoblot and real-time PCR. Formation of GJ plaques was quantified by immunohistochemistry. Compared to control brains, both Cx32 and Cx47 GJ plaques and protein levels were reduced in and around MS lesions, while Cx43 was increased as part of astrogliosis. In the NAWM, Cx32 was significantly reduced along myelinated fibers whereas Cx47 showed increased expression mainly in oligodendrocyte precursor cells (OPCs). However, OPCs showed only limited connectivity to astrocytes. Cx43 showed modestly increased levels in MS NAWM compared to controls, while GJ plaque counts were unchanged. Our findings indicate that oligodendrocyte GJs are affected not only in chronic MS lesions but also in NAWM, where disruption of Cx32 GJs in myelinated fibers may impair myelin structure and function. Moreover, limited O/A GJ connectivity of recruited OPCs in the setting of persistent inflammation and astrogliosis may prevent differentiation and remyelination.
authors.affiliation: Neuroscience Laboratory, The Cyprus Institute of Neurology and Genetics, P.O. Box 23462, 1683 Nicosia, Cyprus.
authors.forename: Kyriaki
authors.initials: K
authors.lastname: Markoullis
authors.forename: Irene
authors.initials: I
authors.lastname: Sargiannidou
authors.forename: Natasa
authors.initials: N
authors.lastname: Schiza
authors.forename: Andreas
authors.initials: A
authors.lastname: Hadjisavvas
authors.forename: Federico
authors.initials: F
authors.lastname: Roncaroli
authors.forename: Richard
authors.initials: R
authors.lastname: Reynolds
authors.forename: Kleopas A
authors.initials: KA
authors.lastname: Kleopa
mesh_terms: D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology; D017630:Connexins / Q000235:genetics / Q000378:metabolism*; D017629:Gap Junctions / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D009103:Multiple Sclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009413:Nerve Fibers, Myelinated / Q000473:pathology*; D009836:Oligodendroglia / Q000378:metabolism
chemical_list: D017630:Connexins