Connexin 43 Astrocytopathy Linked to Rapidly Progressive Multiple Sclerosis and Neuromyelitis Optica

Abstract

BackgroundMultiple 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.Methods/Principal FindingsSamples 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.ConclusionsThese findings suggest that autoantibody-independent astrocytic Cx43 loss may relate to disease aggressiveness and distal oligodendrogliopathy in both MS and NMO.

Multiple Sclerosis: Etiology and Mechanism, with Special Reference to Asians

“…We also found similar changes in extensive lesions of MS and NMO cases that died within 2 years after disease onset (Fig. 5.5) [186]. A significant reduction of Cx32 and Cx47 occurs in active lesions of MOG-induced EAE [187].…”

Chronic Cerebral Hypoperfusion Induced Synaptic Proteome Changes in the rat Cerebral Cortex

“…Among them, GJA1, SLCA2 and Leukocyte surface antigen CD47 (CD47) showed decreased, while APOE, MAP2K1, TF and PEA-15 showed increased expression in CCH rats. Interestingly, downregulation or absence of GJA1 reduced neuronal loss, capillary fragmentation, astrocytosis and microglia activation (Davidson et al, 2013), while reactive astrogliosis increases GJA1 expression (Masaki et al, 2013, Wallach et al, 2014. Moreover, brain microgliosis and astrogliosis are also affected in APOE transgenic mice (Bales et al, 1999) and the absence of APOE dramatically reduced amyloid deposition and the resulting astrogliosis and microgliosis (Ophir et al, 2003).…”

A start codon CMT1X mutation associated with transient encephalomyelitis causes complete loss of Cx32

“…Oligodendrocyte-astrocyte connectivity is disrupted under inflammatory conditions as the main astrocytic partner of Cx47, Cx43, is downregulated [36] and Cx47 membrane expression depends on the interaction with Cx43 [37]. Downregulation of Cx43 was also shown to occur in acutely inflamed human brain [38]. Decreasing numbers of oligodendrocyte-astrocyte GJs in situations of metabolic stress may lead to the CNS phenotypes through impairment of intercellular exchange of ions and small molecules and myelin edema [2] in keeping with the MRI findings of restricted diffusion in CMT1X CNS phenotypes that may resolve within hours, days, or months [7].…”