Gap junction pathology in multiple sclerosis and normal appearing white matter

Neuroscience Laboratory, The Cyprus Institute of Neurology and Genetics, P.O. Box 23462, 1683 Nicosia, Cyprus.
Acta Neuropathologica (Impact Factor: 10.76). 04/2012; 123(6):873-86. DOI: 10.1007/s00401-012-0978-4
Source: PubMed


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.

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Available from: Richard Reynolds, Aug 05, 2014
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    • "In all CNS diseases, immune cells play a critical role in controlling inflammation. However, unresolved inflammation in the CNS can have devastating consequences, including impaired myelination (Akassoglou et al., 1998; Markoullis et al., 2012) sensorimotor deficits (Han et al., 2014), and loss of signaling that contributes to learning and memory (Koster-Patzlaff et al., 2009; Wang and Belousov, 2011). Activated microglia release pro-inflammatory factors, such as ATP (Orellana et al., 2013) and glutamate (Takeuchi et al., 2006), through uHCs that serve to amplify inflammation with devastating effects if left unchecked. "
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    ABSTRACT: Gap junctions (GJs) are conglomerates of intercellular channels that connect the cytoplasm of two or more cells, and facilitate the transfer of ions and small molecules, including second messengers, resulting in metabolic and electrical coordination. In general, loss of gap junctional communication (GJC) has been associated with cellular damage and inflammation resulting in compromise of physiological functions. Recently, it has become evident that GJ channels also play a critical role in the pathogenesis of infectious diseases and associated inflammation. Several pathogens use the transfer of intracellular signals through GJ channels to spread infection and toxic signals that amplify inflammation to neighboring cells. Thus, identification of the mechanisms by which several infectious agents alter GJC could result in new potential therapeutic approaches to reduce inflammation and their pathogenesis.
    Full-text · Article · May 2014 · Frontiers in Cellular Neuroscience

  • No preview · Article · Jun 2013 · Clinical and Experimental Neuroimmunology
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    ABSTRACT: Multiple sclerosis (MS) and neuromyelitis optica (NMO) occasionally have an extremely aggressive and debilitating disease course; however, its molecular basis is unknown. This study aimed to determine a relationship between connexin (Cx) pathology and disease aggressiveness in Asian patients with MS and NMO. Samples included 11 autopsied cases with NMO and NMO spectrum disorder (NMOSD), six with MS, and 20 with other neurological diseases (OND). Methods of analysis included immunohistochemical expression of astrocytic Cx43/Cx30, oligodendrocytic Cx47/Cx32 relative to AQP4 and other astrocytic and oligodendrocytic proteins, extent of demyelination, the vasculocentric deposition of complement and immunoglobulin, and lesion staging by CD68 staining for macrophages. Lesions were classified as actively demyelinating (n=59), chronic active (n=58) and chronic inactive (n=23). Sera from 120 subjects including 30 MS, 30 NMO, 40 OND and 20 healthy controls were examined for anti-Cx43 antibody by cell-based assay. Six NMO/NMOSD and three MS cases showed preferential loss of astrocytic Cx43 beyond the demyelinated areas in actively demyelinating and chronic active lesions, where heterotypic Cx43/Cx47 astrocyte oligodendrocyte gap junctions were extensively lost. Cx43 loss was significantly associated with a rapidly progressive disease course as six of nine cases with Cx43 loss, but none of eight cases without Cx43 loss regardless of disease phenotype, died within two years after disease onset (66.7% vs. 0%, P=0.0090). Overall, five of nine cases with Cx43 loss and none of eight cases without Cx43 loss had distal oligodendrogliopathy characterized by selective myelin associated glycoprotein loss (55.6% vs. 0.0%, P=0.0296). Loss of oligodendrocytic Cx32 and Cx47 expression was observed in most active and chronic lesions from all MS and NMO/NMOSD cases. Cx43-specific antibodies were absent in NMO/NMOSD and MS patients. These findings suggest that autoantibody-independent astrocytic Cx43 loss may relate to disease aggressiveness and distal oligodendrogliopathy in both MS and NMO.
    Full-text · Article · Aug 2013 · PLoS ONE
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