Insights into peptidylarginine deiminase expression and citrullination pathways

Yu, Karen; Proost, Paul

doi:10.1016/j.tcb.2022.01.014

Cited by 42 publications

(48 citation statements)

References 114 publications

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“…However, PC alters protein functions [9,14,50]. Furthermore, polypeptides relevant to neurodegeneration, such as amyloid β peptide, GFAP, vimentin, FET proteins, myelin proteins, and others, have been shown to be citrullinated [9,14,51,52]. Therefore, we speculate that PC in the ALS mouse models alters protein function and modulate the disease.…”

Section: Discussionmentioning

confidence: 94%

“…How these changes contribute to neurodegeneration is not yet known. However, PC alters protein functions [9,14,50]. Furthermore, polypeptides relevant to neurodegeneration, such as amyloid β peptide, GFAP, vimentin, FET proteins, myelin proteins, and others, have been shown to be citrullinated [9,14,51,52].…”

Section: Discussionmentioning

confidence: 99%

“…However, they are activated at high calcium levels (1-10 mM). Once activated, PADs citrullinate a wide range of protein substrates thus regulating various cellular processes including cell signaling, immune responses, gene regulation, and myelination [14]. PADs are differentially expressed in tissues, and they have common as well as distinct substrate specificities [7].…”

Section: Introductionmentioning

confidence: 99%

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Protein citrullination marks myelin protein aggregation and disease progression in mouse ALS models

Yusuf

Qiao

Parsi

et al. 2022

acta neuropathol commun

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Increased protein citrullination (PC) and dysregulated protein arginine deiminase (PAD) activity have been observed in several neurodegenerative diseases. PC is a posttranslational modification catalyzed by the PADs. PC converts peptidyl-arginine to peptidyl-citrulline, thereby reducing the positive charges and altering structure and function of proteins. Of the five PADs, PAD2 is the dominant isoform in the central nervous system (CNS). Abnormal PC and PAD dysregulation are associated with numerous pathological conditions, including inflammatory diseases and neurodegeneration. Animal model studies have shown therapeutic efficacy from inhibition of PADs, thus suggesting a role of PC in pathogenesis. To determine whether PC contribute to amyotrophic lateral sclerosis (ALS), a deadly neurodegenerative disease characterized by loss of motor neurons, paralysis, and eventual death, we investigated alterations of PC and PAD2 in two different transgenic mouse models of ALS expressing human mutant SOD1G93A and PFN1C71G, respectively. PC and PAD2 expression are altered dynamically in the spinal cord during disease progression in both models. PC and PAD2 increase progressively in astrocytes with the development of reactive astrogliosis, while decreasing in neurons. Importantly, in the spinal cord white matter, PC accumulates in protein aggregates that contain the myelin proteins PLP and MBP. PC also accumulates progressively in insoluble protein fractions during disease progression. Finally, increased PC and PAD2 expression spatially correlate with areas of the CNS with the most severe motor neuron degeneration. These results suggest that altered PC is an integral part of the neurodegenerative process and potential biomarkers for disease progression in ALS. Moreover, increased PC may contribute to disease-associated processes such as myelin protein aggregation, myelin degeneration, and astrogliosis.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Protein citrullination marks myelin protein aggregation and disease progression in mouse ALS models

Yusuf

Qiao

Parsi

et al. 2022

acta neuropathol commun

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“…Thus, PAD4 is downstream of ROS and calcium signaling during NETosis. PAD4 induces chromatin decondensation by catalyzing the conversion of arginine residues on histones to citrulline residues and is a key trigger of NETosis ( 73 – 75 ). Of course, NET formation can occur independent of PAD4 ( 66 ).…”

Section: Mechanisms Underlying the Formation Of Neutrophil Extracellu...mentioning

confidence: 99%

The role of extracellular traps in ischemia reperfusion injury

Zhang

et al. 2022

Front. Immunol.

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In response to strong signals, several types of immune cells release extracellular traps (ETs), which are web-like structures consisting of DNA decorated with various protein substances. This process is most commonly observed in neutrophils. Over the past two decades, ET formation has been recognized as a unique mechanism of host defense and pathogen destruction. However, the role of ETs in sterile inflammation has only been studied extensively in recent years. Ischemia reperfusion injury (IRI) is a type of sterile inflammatory injury. Several studies have reported that ETs have an important role in IRI in various organs. In this review, we describe the release of ETs by various types of immune cells and focus on the mechanism underlying the formation of neutrophil ETs (NETs). In addition, we summarize the role of ETs in IRI in different organs and their effects on tumors. Finally, we discuss the value of ETs as a potential therapeutic target for organ IRI and present possible challenges in conducting studies on IRI-related ETs as well as future research directions and prospects.

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“…The following table shows representative compounds tested for PAD4 inhibition and the biological data obtained from testing representative examples. …”

Section: Important Compound Classesmentioning

confidence: 99%