Retinal deimination in aging and disease

Abstract

SummaryDeimination is a posttranslational modification and refers to the conversion of protein bound arginine into citrulline. In the retina, deimination is predominantly catalyzed by Peptidylarginine deiminase type 2 (PAD2). PAD2 expression and deimination are found in many different retinal layers: choroid, retinal pigment epithelium (RPE), photoreceptors, inner plexiform layer, inner nuclear layer, and retinal ganglion cell (RGC) layer. Although decreased retinal deimination and PAD2 expression have been found during normal aging, elevated PAD2 expression and deimination have been observed in agerelated neurodegenerative diseases. The role of deimination in normal physiology and in late-onset and progressive ocular or retinal degenerative diseases, such as glaucoma and experimental autoimmune encephalomyelitis remains to be elucidated.

Proteomics Analyses of Human Optic Nerve Head Astrocytes Following Biomechanical Strain

“…Zhao et al (57) and Fuchshofer et al (58) investigated the role of TGF-␤, proposing its importance in the pathogenesis of glaucoma. Bhattacharya et al (53) found a positive link between the presence of PAD2 and glaucoma and in more recent research this group has outlined the occurrence of retinal deiminization (59,60), further confirming the post-translational effects and their role in glaucoma. Tezel and colleagues (14,61,62) have used proteomics to determine the role of oxidative stress on retinal proteins in glaucoma, the influence of hemoglobin expression and regulation, (16) and the importance of the complement pathway (62).…”

A simple but efficient electrochemical method to assay protein arginine deiminase 4

“…One of the main reasons is that the upregulation of PAD4 has been especially found in rheumatoid arthritis (RA) patients, which is believed to play causative role in the onset and progression of RA [6][7][8][9]. Besides, aberrant increase of PAD 4 has also been involved in multiple sclerosis, glaucoma and even cancers [10][11][12]. Therefore, with the deciphering the relation between PAD4 and different disease models [13,14], PAD4 has emerged as a potential therapeutic target for human diseases.…”

Deimination restores inner retinal visual function in murine demyelinating disease

“…In our prior studies, we found that PAD2 expression and deimination, in response to pressure, is decreased in RGCs (M. EnriquezAlgeciras and D. Ding, unpublished observations) in contrast with an increase in astrocytes (34,36). This opposite deimination pattern in astrocytes and RGCs was conjectured earlier (15). Insults such as hydrostatic pressure, hypoxia, and chemokines on an isolated mixed population of cells derived from CD1 mouse brain show similar increase and decrease in deimination in the astrocytes and neurons (data not shown).…”

“…In the retina, the hyperdeiminated regions are less pronounced than in the brain and are likely contributed by retinal epithelial cells or other glial cells. A change in the deimination is also expected to alter protein-protein interactions and, as a consequence, functional biological pathways (15). It is important to note that no known enzyme exists for reversal of deimination, rendering it a long-term modification to be reversed by protein turnover.…”

“…For example, one important and irreversible PTM is deimination, in which protein-bound arginine is converted into citrulline (14,15) by one of the peptidylarginine deiminases (PADs). Hyperdeiminated regions and increased levels of the enzyme PAD2 have been found in the brains of individuals with MS (16,17), and myelin basic protein (MBP) derived from MS patients is heavily deiminated (16) and shows enhanced susceptibility to proteolysis (18).…”