Abstract
Ermin is an actin‐binding protein found almost exclusively in the central nervous system (CNS) as a component of myelin sheaths. Although Ermin has been predicted to play a role in the formation and stability of myelin sheaths, this has not been directly examined in vivo. Here, we show that Ermin is essential for myelin sheath integrity and normal saltatory conduction. Loss of Ermin in mice caused de‐compacted and fragmented myelin sheaths and led to slower conduction along with progressive neurological deficits. RNA sequencing of the corpus callosum, the largest white matter structure in the CNS, pointed to inflammatory activation in aged Ermin‐deficient mice, which was corroborated by increased levels of microgliosis and astrogliosis. The inflammatory milieu and myelin abnormalities were further associated with increased susceptibility to immune‐mediated demyelination insult in Ermin knockout mice. Supporting a possible role of Ermin deficiency in inflammatory white matter disorders, a rare inactivating mutation in the
ERMN
gene was identified in multiple sclerosis patients. Our findings demonstrate a critical role for Ermin in maintaining myelin integrity. Given its near‐exclusive expression in myelinating oligodendrocytes, Ermin deficiency represents a compelling “inside‐out” model of inflammatory dysmyelination and may offer a new paradigm for the development of myelin stability‐targeted therapies.
A working model for the sequence of pathological events in Ermin‐deficient mice (1) Loss of Ermin leads to compromised myelin that is de‐compacted, out folded, and fragmented; (2) As Ermin‐deficient mice age, augmentation of myelin fragmentation and myelin sheath breakdown lead to loss of myelinating oligodendrocytes. Due to compromised myelin sheaths and oligodendrocyte function, loss of trophic support to axons also leads to axonal damage and degeneration; (3) Excessive myelin debris along with oligodendrocyte loss and axonal damage/degeneration triggers white matter inflammation. Activated microglia and astrocytes further exacerbate cell loss. This ensuing inflammation may act as a feed‐forward demyelinating insult causing further damage to unhealthy myelin sheaths in Ermin deficient mice.