Ermin deficiency leads to compromised myelin, inflammatory milieu, and susceptibility to demyelinating insult.

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.

• Authors: Amin Ziaei, Marta Garcia-Miralles, Carola I Radulescu, Harwin Sidik, Aymeric Silvin, Han-Gyu Bae, Carine Bonnard, Nur Amirah Binte Mohammad Yusof, Costanza Ferrari Bardile, Liang Juin Tan, Alvin Yu Jin Ng, Sumanty Tohari, Leila Dehghani, Lily Henry, Xin Yi Yeo, Sejin Lee, Byrappa Venkatesh, Sarah R Langley, Vahid Shaygannejad, Bruno Reversade, Sangyong Jung, Florent Ginhoux, Mahmoud A Pouladi
• Journal: Brain pathology (Zurich, Switzerland) (Brain Pathol) Vol. 32 Issue 5 Pg. e13064 (09 2022) ISSN: 1750-3639 [Electronic] Switzerland
• PMID: 35285112 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.

Topics

• Animals
• Central Nervous System (metabolism)
• Demyelinating Diseases (genetics, metabolism)
• Mice
• Multiple Sclerosis (metabolism)
• Myelin Sheath (metabolism)
• Oligodendroglia (metabolism)