PAD2-Mediated Citrullination Contributes to Efficient Oligodendrocyte Differentiation and Myelination

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Ana Mendanha Falcão, Mandy Meijer, Antonella Scaglione, Puneet Rinwa, Eneritz Agirre, Jialiang Liang, Sara C Larsen, Abeer Heskol, Rebecca Frawley, Michael Klingener, Manuel Varas-Godoy, Alexandre A S F Raposo, Patrik Ernfors, Diogo S Castro, Michael L Nielsen, Patrizia Casaccia, Gonçalo Castelo-Branco

Citrullination, the deimination of peptidylarginine residues into peptidylcitrulline, has been implicated in the etiology of several diseases. In multiple sclerosis, citrullination is thought to be a major driver of pathology through hypercitrullination and destabilization of myelin. As such, inhibition of citrullination has been suggested as a therapeutic strategy for MS. Here, in contrast, we show that citrullination by peptidylarginine deiminase 2 (PAD2) contributes to normal oligodendrocyte differentiation, myelination, and motor function. We identify several targets for PAD2, including myelin and chromatin-related proteins, implicating PAD2 in epigenomic regulation. Accordingly, we observe that PAD2 inhibition and its knockdown affect chromatin accessibility and prevent the upregulation of oligodendrocyte differentiation genes. Moreover, mice lacking PAD2 display motor dysfunction and a decreased number of myelinated axons in the corpus callosum. We conclude that citrullination contributes to proper oligodendrocyte lineage progression and myelination.

Original languageEnglish
JournalCell Reports
Volume27
Issue number4
Pages (from-to)1090-1102.e10
ISSN2211-1247
DOIs
Publication statusPublished - 23 Apr 2019

Bibliographical note

Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

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