Connexin pathology in acute multiple sclerosis, B aló's disease and neuromyelitis optica

Multiple sclerosis ( MS ), neuromyelitis optica ( NMO ) and B aló's disease ( BD ) are inflammatory demyelinating diseases of the central nervous system ( CNS ). We previously reported aquaporin‐4 ( AQP 4) loss without perivascular deposition of complement or immunoglobulin in demyelinating diseases, suggesting that astrocytic damage could be a common denominator in heterogeneous demyelinating conditions. To investigate the relationship between astrocytopathy and demyelination, we focused on connexins ( C xs), which form gap junction channels between astrocytes and oligodendrocytes, and maintain myelination and homeostasis in the CNS . We pathologically evaluated the expression of astrocytic C x43/ C x30 and oligodendrocytic C x47/ C x32 in autopsied tissue samples from MS , NMO and BD patients. In all BD samples, astrocytic C x43 and oligodendrocytic C x32/ C x47 expression was diminished in both demyelinated and preserved myelin layers. In the leading edge of BD lesions, C x43 and AQP 4 loss preceded C x32/ C x47 loss. Half of the NMO and MS samples showed preferential loss of astrocytic C x43 in actively demyelinating and chronic active lesions, where heterotypic C x43/ C x47 astrocyte‐oligodendrocyte gap junctions were lost. Cases with C x43 loss were significantly associated with rapid disease progression (death within 2 years after onset), regardless of the disease phenotype. Pathologically, C x43 loss was frequently accompanied by distal oligodendrogliopathy. These findings suggest that C x43 astrocytopathy can occur in MS , BD and NMO . Furthermore, astrocytic C x43 loss might be associated with disease aggressiveness and distal oligodendrogliopathy, not only in BD ,but also MS and NMO . Early disruption of astrocytic foot processes could precede demyelination and contribute to the pathogenesis of demyelinating disorders.