Peptidylarginine deiminases: novel drug targets for prevention of neuronal damage following hypoxic ischemic insult (HI) in neonates

Neonatal hypoxic ischaemic (HI) injury frequently causes neural impairment in surviving infants. Our knowledge of the underlying molecular mechanisms is still limited. Protein deimination is a post‐translational modification caused by Ca+2‐regulated peptidylarginine deiminases (PADs), a group of fiv...

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Published in:Journal of neurochemistry 2014-08, Vol.130 (4), p.555-562
Main Authors: Lange, Sigrun, Rocha‐Ferreira, Eridan, Thei, Laura, Mawjee, Priyanka, Bennett, Kate, Thompson, Paul R., Subramanian, Venkataraman, Nicholas, Anthony P., Peebles, Donald, Hristova, Mariya, Raivich, Gennadij
Format: Article
Language:English
Subjects:
Animals
Animals, Newborn
Babies
Brain Infarction - drug therapy
Brain Infarction - pathology
Cell Death - drug effects
Central Nervous System Bacterial Infections - drug therapy
Central Nervous System Bacterial Infections - pathology
Enzyme Inhibitors - pharmacology
Enzymes
Hydrolases - antagonists & inhibitors
Hypoxia-Ischemia, Brain - pathology
Hypoxia-Ischemia, Brain - prevention & control
hypoxic ischaemic encephalopathy
Immunohistochemistry
In Situ Nick-End Labeling
Ischemia
Isoenzymes - antagonists & inhibitors
Isoenzymes - metabolism
lipopolysaccharide
Lipopolysaccharides
Mice
Mice, Inbred C57BL
microglia
Microglia - drug effects
neonatal
Neurochemistry
Neurons - drug effects
Neurons - pathology
Original
Ornithine - analogs & derivatives
Ornithine - toxicity
peptidylarginine deiminases
Pharmacology
protein deimination/citrullination
Protein-Arginine Deiminases
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Summary:Neonatal hypoxic ischaemic (HI) injury frequently causes neural impairment in surviving infants. Our knowledge of the underlying molecular mechanisms is still limited. Protein deimination is a post‐translational modification caused by Ca+2‐regulated peptidylarginine deiminases (PADs), a group of five isozymes that display tissue‐specific expression and different preference for target proteins. Protein deimination results in altered protein conformation and function of target proteins, and is associated with neurodegenerative diseases, gene regulation and autoimmunity. In this study, we used the neonatal HI and HI/infection [lipopolysaccharide (LPS) stimulation] murine models to investigate changes in protein deimination. Brains showed increases in deiminated proteins, cell death, activated microglia and neuronal loss in affected brain areas at 48 h after hypoxic ischaemic insult. Upon treatment with the pan‐PAD inhibitor Cl‐amidine, a significant reduction was seen in microglial activation, cell death and infarct size compared with control saline or LPS‐treated animals. Deimination of histone 3, a target protein of the PAD4 isozyme, was increased in hippocampus and cortex specifically upon LPS stimulation and markedly reduced following Cl‐amidine treatment. Here, we demonstrate a novel role for PAD enzymes in neural impairment in neonatal HI Encephalopathy, highlighting their role as promising new candidates for drug‐directed intervention in neurotrauma. Hypoxic Ischaemic Insult (HI) results in activation of peptidylarginine deiminases (PADs) because of calcium dysregulation. Target proteins undergo irreversible changes of protein bound arginine to citrulline, resulting in protein misfolding. Infection in synergy with HI causes up‐regulation of TNFα, nuclear translocation of PAD4 and change in gene regulation as a result of histone deimination. Pharmacological PAD inhibition significantly reduced HI brain damage. Hypoxic Ischaemic Insult (HI) results in activation of peptidylarginine deiminases (PADs) because of calcium dysregulation. Target proteins undergo irreversible changes of protein bound arginine to citrulline, resulting in protein misfolding. Infection in synergy with HI causes up‐regulation of TNFα, nuclear translocation of PAD4 and change in gene regulation as a result of histone deimination. Pharmacological PAD inhibition significantly reduced HI brain damage.
ISSN:0022-3042
1471-4159
DOI:10.1111/jnc.12744