Zinc homeostasis and zinc signaling in white matter development and injury

Zinc is an essential dietary micronutrient that is abundant in the brain with diverse roles in development, injury, and neurological diseases. With new imaging tools and chelators selectively targeting zinc, the field of zinc biology is rapidly expanding. The importance of zinc homeostasis is now well recognized in neurodegeneration, but there is emerging data that zinc may be equally important in white matter disorders. This review provides an overview of zinc biology, including a discussion of clinical disorders of zinc deficiency, different zinc pools, zinc biomarkers, and methods for measuring zinc. It emphasizes our limited understanding of how zinc is regulated in oligodendrocytes and white matter. Gaps in knowledge about zinc transporters and zinc signaling are discussed. Zinc-induced oligodendrocyte injury pathways relevant to white matter stroke, multiple sclerosis, and white matter injury of prematurity are reviewed and examples of zinc-dependent proteins relevant to myelination highlighted. Finally, a novel ratiometric zinc sensor is reviewed, revealing new information about mobile zinc during oligodendrocyte differentiation. With a better understanding of zinc biology in oligodendrocytes, new therapeutic targets for white matter disorders may be possible and the necessary tools to appropriately study zinc are finally available.