Oligodendrocyte Piezo2 is a regulator of age-dependent myelin integrity and dysregulated in multiple sclerosis.

Studies on the mechanosensitive ion channel Piezo2 largely focus on its role in the peripheral nervous system, particularly in touch and pain sensation. Here, we investigate Piezo2 function in the anterior visual pathway of the central nervous system with a focus on oligodendrocyte (OL) biology and myelin integrity. Using single-nucleus RNA sequencing, we identify Piezo2 expression in late differentiated OLs of the murine optic nerve, with minor expression in retinal ganglion cells. OL-specific Piezo2 deficiency results in age-dependent motor impairment and selective disruption of myelin compaction in small-caliber optic nerve axons, a fiber population known to be particularly vulnerable in demyelinating disease. Differential gene expression analysis further indicates that Piezo2 regulates myelin compaction and white matter integrity in mature OLs. Consistent with these findings, OL-encoded PIEZO2 expression is reduced in optic nerve lesion areas from multiple sclerosis patients, highlighting a convergent mechanism of small-caliber fiber vulnerability. Together, these data identify Piezo2 as an age-related regulator of OL function and myelin integrity, with potential relevance for preserving white matter structure in multiple sclerosis.