Abstract
SummaryCitrullination, 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.
Highlights
The conversion of a peptidylarginine into a peptidylcitrulline can introduce profound changes in the structure and function of the modified protein
Padi2 expression is found in OL precursor cells (OPCs), increases in committed OL precursors (COPs) and newly formed OLs (NFOLs), and peaks at more mature stages (Figure S1A)
To further investigate the pattern of expression of Padi2 during early OL lineage progression, we cultured OPCs isolated from postnatal day (P) 1 to P4 brains of the transgenic mouse line Pdgfra-histone 2b (H2B)-GFP (Klinghoffer et al, 2002) in which nuclear GFP expression is under the control of the endogenous Pdgfra promoter locus
Summary
The conversion of a peptidylarginine into a peptidylcitrulline can introduce profound changes in the structure and function of the modified protein. This posttranslational modification, known as protein citrullination or deimination, is calcium dependent and is mediated by the family of enzymes called peptidylarginine deiminases (Padis or PADs) (Wang and Wang, 2013). In the central nervous system (CNS), PAD2 is the most prevalent expressed PAD and occurs preferentially in oligodendrocytes (OLs) and other glial cells (Zeisel et al, 2015). OLs arise at postnatal stages from the differentiation of OL precursor cells (OPCs), and their most prominent function is the formation of the myelin sheath, an electrical insulating layer for the axons, essential for proper neuronal communication and CNS function (Bergles and Richardson, 2015)
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