In this issue of Neuron, Estevez,

Pusch, and colleagues Tariquidar in vitro use a biochemical approach to identify ClC-2 as the crucial GlialCAM binding partner, thus reinvigorating the link between cystic leukoencephalopathies and ClC-2 ( Jeworutzki et al., 2012). Their ensuing discovery that GlialCAM targets ClC-2 to cell contacts together with the phenotype of the ClC-2 knockout mouse strongly supports the hypothesis that altered ion flux across oligodendrocyte membranes leads to myelin vacuolization in MLC. The expression of GlialCAM and ClC-2 in oligodendrocytes is consistent with the major pathology of MLC, but how could loss of MLC1, which is not expressed in oligodendrocytes, cause a similar phenotype? Genetic defects in MLC1, GlialCAM, and ClC-2 induce similar glial and myelin pathologies in both humans and mice, suggesting that all three proteins contribute to a Selleck Venetoclax common functional process. GlialCAM trafficks both ClC-2 and MLC1 to cell-cell junctions and has a robust effect on ClC-2 electrophysiological function; however, no biochemical or functional interaction between ClC-2 and MLC1 could be detected, and MLC1 expression and localization are not affected in the ClC-2

knockout mouse. Nevertheless, it remains possible that MLC1 and ClC-2 could interact indirectly. Indeed, an indirect interaction through GlialCAM could juxtapose MLC1 and ClC-2 across astrocyte-oligodendrocyte cell contacts (Figure 1), thus bringing MLC1 to the site of major pathology in the disease. But by what mechanism does the disease occur? It is known that ion movement through the glial syncytium

is in delicate balance. Upsetting this balance by disruption of either gap junctions (which facilitate intraglial ion movement) or Kir4.1 potassium channels (which facilitate glial-extracellular ion movement) leads to myelin vacuolation. Thus, it is likely much that ClC-2, in parallel to Kir4.1, contributes to ion homeostasis in the narrow extracellular spaces. While the precise mechanism of myelin vacuolation has not been defined, it probably arises from osmotic imbalances associated with the defect in ion homeostasis (Brignone et al., 2011). But what is the function of MLC1? Is it an ion channel as well? This remains a mystery and will require further study of MLC1 and investigations of how loss of MLC1 influences ion permeability across membranes of individual astrocytes and the glial syncytium. In addition to changing ClC-2 localization, GlialCAM has an amazing effect on ClC-2 currents. In heterologous expression systems, coexpression of GlialCAM and ClC-2 results in large currents that retain ClC-2′s characteristic anionic selectivity, but lack its signature rectification and slow activation by hyperpolarization.