Astrocytes, the most numerous cells of the central nervous system, exert critical functions for brain homeostasis. To this purpose, astrocytes generate a highly interconnected intercellular network allowing rapid exchange of
ions and metabolites through gap junctions, adjoined channels composed of hexamers of
connexin (Cx)
proteins, mainly
Cx43. Functional alterations of Cxs and gap junctions have been observed in several neuroinflammatory/
neurodegenerative diseases. In the rare leukodystrophy
megalencephalic leukoencephalopathy with subcortical cysts (MLC), astrocytes show defective control of ion/fluid exchanges causing
brain edema, fluid
cysts, and astrocyte/myelin vacuolation. MLC is caused by mutations in MLC1, an astrocyte-specific
protein of elusive function, and in GlialCAM, a MLC1 chaperon. Both
proteins are highly expressed at perivascular astrocyte end-feet and astrocyte-astrocyte contacts where they interact with zonula occludens-1 (ZO-1) and
Cx43 junctional
proteins. To investigate the possible role of
Cx43 in MLC pathogenesis, we studied
Cx43 properties in
astrocytoma cells overexpressing wild type (WT) MLC1 or MLC1 carrying pathological mutations. Using biochemical and electrophysiological techniques, we found that WT, but not mutated, MLC1 expression favors intercellular communication by inhibiting
extracellular-signal-regulated kinase 1/2 (ERK1/2)-mediated
Cx43 phosphorylation and increasing
Cx43 gap-junction stability. These data indicate MLC1 regulation of
Cx43 in astrocytes and
Cx43 involvement in MLC pathogenesis, suggesting potential target pathways for therapeutic interventions.