Glial Ion Channels in Myelin Pathophysiology: Insights from Leukodystrophies

Leukodystrophies (LDs) constitute a heterogeneous group of genetic diseases in which mutations in glial cell genes lead to alterations in myelin formation and/or maintenance, ultimately causing white matter dysfunction. Increasing evidence on the genetic basis of LDs has revealed that proteins expressed not only by myelin-forming oligodendrocytes, but also by other glial cell types, play essential roles in myelination. By elucidating disease mechanisms, these studies have uncovered novel cellular and molecular contributors to myelin biogenesis and function, including ion channels. This is exemplified by the recent identification of mutations in the TMEM63A gene, which encodes the homonymous mechanosensitive channel, as the causative factor of the rare hypomyelinating LD HLD19 and by mutations in the chloride channel ClC-2 as responsible for the development of the vacuolating ClC2 LD. Together, this evidence has opened new perspectives on the crucial role of mechanosensitivity and ionic homeostasis for proper myelin development and structural integrity. In this review, we summarize recent advances on the role of glial ion channels in healthy white matter development and preservation, as well as their direct and indirect contributions to LD pathomechanisms. Finally, we discuss emerging therapeutic implications of these studies for LDs and other demyelinating conditions and emphasize the considerable potential of a cross-pathological, integrative approach to uncover shared and disease-specific mechanisms of demyelination.