CLCN2-related Leukoencephalopathy
https://www.nature.com/articles/s41380-025-03159-x
Leukoencephalopathies are a group of disorders where the myelin surrounding nerves is lost or damaged. Myelin production and repair depend on the maturation of oligodendrocytes. Why these cells fail to develop properly in certain conditions is still poorly understood. The present study focused on the support cells called astrocytes and explored the effects of the astrocytic ClC-2 protein on myelin repair in the condition CLCN2-related leukoencephalopathy (CC2L). Using both mouse models and human stem cell-derived cellular models, researchers found that when astrocytes lack ClC-2 (encoded by the CLCN2 gene), they cannot properly support the maturation of oligodendrocytes, thus affecting myelin repair. They further showed that ClC2-deficiency caused astrocytes to accumulate a protein called SPP1 (osteopontin). High levels of SPP1 interacted with the CD44 molecule present on oligodendrocytic cells and blocked remyelination. Strategies to reduce SPP1 or block the SPP1/CD44 interaction restored myelin growth. Similarly, restoring ClC-2 expression in astrocytes improved neurological outcomes in mice. Overall, the study revealed that astrocytes, not just oligodendrocytes, play an active role in myelin repair. Data suggest that astrocytic ClC-2 is a regulator of white matter health, opening the path to further explorations.