Peptidylarginine Deiminases as Drug Targets in Neonatal Hypoxic–Ischemic Encephalopathy

Lange, Sigrun

doi:10.3389/fneur.2016.00022

Cited by 21 publications

(23 citation statements)

References 132 publications

(150 reference statements)

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“…Previous studies on in vivo models of CNS damage showed that PAD-upregulation and increased protein deimination lead to vast neuronal death which was preventable by pharmacological PAD inhibition, significantly reducing neuroinflammatory responses and histone H3 deimination, which has implications in gene regulation [23,[33][34][35]. In addition we have observed increased PAD expression during disease progression in tau mutation mouse models compared to age-matched controls [36].…”

Section: Introductionsupporting

confidence: 53%

“…Increased EV shedding from cancer cells, facilitated in part by upregulated PAD expression, also acts as a protective mechanism of cancer cells to expel chemotherapeutic drugs. Functional roles for PADs in CNS damage, and neuroprotective pharmacological intervention in vivo, have recently been established and provide evidence for crucial roles of PAD-mediated mechanisms in neuroinflammation [32][33][34][35]. Pilot studies using human iPSC neuronal models, derived from patients' fibroblasts carrying neurodegenerative disease mutations, show increased PAD activity and PAD-mediated deimination that will also affect downstream EV release [36].…”

Section: Discussionmentioning

confidence: 99%

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Peptidylarginine Deiminases as Mediators of Microvesicular Release - Novel Therapeutic Interventions

Lange¹,

Kholia²,

Kosgodage³

et al. 2017

Preprint

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Extracellular vesicle (EV) release, which occurs in most eukaryotic cells, has recently been associated with peptidylarginine deiminase (PAD)-driven protein deimination. Evidence points to the involvement of deiminated cytoskeletal proteins and changes in histone deimination. Both PADs and EVs are associated with various pathologies including cancers, autoimmune and neurodegenerative diseases. The elevated PAD expression observed in cancers may contribute to increase in EV shedding observed from cancer cells, contributing to cancer progression. Similarly, elevated PAD expression observed in neurodegenerative diseases may cause increased EV shedding and spread of neurodegenerative EV cargo, contributing to disease progression and pathologies. Pharmacological inhibition of PAD-mediated deimination using pan-PAD inhibitor Cl-amidine, reduced cellular EV release in prostate cancer cells, rendering them significantly more susceptible to chemotherapeutic drugs. Studies on models of central nervous system damage have demonstrated critical functional roles for PADs and neuroprotective effects using PAD inhibitors in vivo, while human neurodegenerative iPSC in vitro models showed evidence of increased protein deimination. Besides using refined PAD inhibitors to selectively manipulate EV biogenesis for novel combination therapies in cancer treatment, we also speculate how EV biogenesis could be targeted via the newly identified PAD-pathway to ameliorate neurodegenerative disease progression.

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Section: Introductionsupporting

confidence: 53%

Section: Discussionmentioning

confidence: 99%

Peptidylarginine Deiminases as Mediators of Microvesicular Release - Novel Therapeutic Interventions

Lange¹,

Kholia²,

Kosgodage³

et al. 2017

Preprint

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“…Increased levels of deiminated histone H3 were here observed in the dentate gyrus as well as in cortex of the pre-motor PD brains. Such increase in citH3 positive detection may be of considerable importance in the neuroinflammatory environment; indeed, previous studies of CNS injury, including via hypoxic damage, have shown that pharmacological inhibition of PADs, and associated reduction of citH3, correlates with neuroprotective effects [119][120][121].…”

Section: Discussionmentioning

confidence: 95%

Protein Deimination Signatures in Plasma and Plasma-EVs and Protein Deimination in the Brain Vasculature in a Rat Model of Pre-Motor Parkinson’s Disease

Sancandi¹,

Uysal-Onganer

Kraev

et al. 2020

IJMS

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The identification of biomarkers for early diagnosis of Parkinson's disease (PD) is of pivotal importance for improving approaches for clinical intervention. The use of translatable animal models of pre-motor PD therefore offers optimal opportunities for novel biomarker discovery in vivo. Peptidylarginine deiminases (PADs) are a family of calcium-activated enzymes that contribute to protein misfolding through post-translational deimination of arginine to citrulline. Furthermore, PADs are an active regulator of extracellular vesicle (EV) release. Both protein deimination and extracellular vesicles (EVs) are gaining increased attention in relation to neurodegenerative diseases, including in PD, while roles in pre-motor PD have yet to be investigated. The current study aimed at identifying protein candidates of deimination in plasma and plasma-EVs in a rat model of pre-motor PD, to assess putative contributions of such post-translational changes in the early stages of disease. EV-cargo was further assessed for deiminated proteins as well as three key micro-RNAs known to contribute to inflammation and hypoxia (miR21, miR155, and miR210) and also associated with PD. Overall, there was a significant increase in circulating plasma EVs in the PD model compared with sham animals and inflammatory and hypoxia related microRNAs were significantly increased in plasma-EVs of the pre-motor PD model. A significantly higher number of protein candidates were deiminated in the pre-motor PD model plasma and plasma-EVs, compared with those in the sham animals. KEGG (Kyoto encyclopedia of genes and genomes) pathways identified for deiminated proteins in the pre-motor PD model were linked to "Alzheimer's disease", "PD", "Huntington's disease", "prion diseases", as well as for "oxidative phosphorylation", "thermogenesis", "metabolic pathways", "Staphylococcus aureus infection", gap junction, "platelet activation", "apelin signalling", "retrograde endocannabinoid signalling", "systemic lupus erythematosus", and "non-alcoholic fatty liver disease". Furthermore, PD brains showed significantly increased staining for total deiminated proteins in the brain vasculature in cortex and hippocampus, as well as increased immunodetection of deiminated histone H3 in dentate gyrus and cortex. Our findings identify EVs and post-translational protein deimination as novel biomarkers in early pre-motor stages of PD. Figure 2. EV characterisation from rat plasma. (A) Representative Nanosight graphs showing nanoparticle tracking analysis (NTA) analysis of plasma EV profiles from sham-treated rats (Sham; n = 3). (B) Representative Nanosight graphs showing NTA analysis of plasma EV profiles from the premotor PD rat models (PD; n = 3). (C) Western blotting (WB) confirms that rat plasma-EVs are positive for the EV-specific markers CD63 and flotillin-1 (Flot-1); the molecular weight standard is indicated in kilo Daltons (kDa). (D,E) Transmission electron microscopy (TEM) images showing EVs isolated from sham (D) and pre-motor PD model (PD; (E)) rat plasma, revea...

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“…Hypoxia related pathways may be of considerable relevance due to the hypoxic core of a tumour mass, which also contains the therapy resistant glioma stem-like cells, a well-recognized problem in the standard treatment of GBM tumours [10,11]. PAD activation has indeed been linked to hypoxia in the CNS [53][54][55] and deiminated KEGG (Kyoto Encyclopedia of Genes and Genomes) protein pathways for HIF-1 regulation have been identified to be enriched in animal models of hypoxia-and cancer-resistance [56,57]. PADs also modulate neuronal stem cell growth and death [58], which is of importance considering that GBM tumour invasion, progression and chemo-resistance of recurrent GBM are partly linked to stem-ness [59,60].…”

Section: Introductionmentioning

confidence: 99%

Peptidylarginine Deiminase Isozyme-Specific PAD2, PAD3 and PAD4 Inhibitors Differentially Modulate Extracellular Vesicle Signatures and Cell Invasion in Two Glioblastoma Multiforme Cell Lines

Uysal-Onganer

MacLatchy

Rayan

et al. 2020

IJMS

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Glioblastoma multiforme (GBM) is an aggressive adult brain tumour with poor prognosis. Roles for peptidylarginine deiminases (PADs) in GBM have recently been highlighted. Here, two GBM cell lines were treated with PAD2, PAD3 and PAD4 isozyme-specific inhibitors. Effects were assessed on extracellular vesicle (EV) signatures, including EV-microRNA cargo (miR21, miR126 and miR210), and on changes in cellular protein expression relevant for mitochondrial housekeeping (prohibitin (PHB)) and cancer progression (stromal interaction molecule 1 (STIM-1) and moesin), as well as assessing cell invasion. Overall, GBM cell-line specific differences for the three PAD isozyme-specific inhibitors were observed on modulation of EV-signatures, PHB, STIM-1 and moesin protein levels, as well as on cell invasion. The PAD3 inhibitor was most effective in modulating EVs to anti-oncogenic signatures (reduced miR21 and miR210, and elevated miR126), to reduce cell invasion and to modulate protein expression of pro-GBM proteins in LN229 cells, while the PAD2 and PAD4 inhibitors were more effective in LN18 cells. Furthermore, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways for deiminated proteins relating to cancer, metabolism and inflammation differed between the two GBM cell lines. Our findings highlight roles for the different PAD isozymes in the heterogeneity of GBM tumours and the potential for tailored PAD-isozyme specific treatment.

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Peptidylarginine Deiminases as Drug Targets in Neonatal Hypoxic–Ischemic Encephalopathy

Cited by 21 publications

References 132 publications

Peptidylarginine Deiminases as Mediators of Microvesicular Release - Novel Therapeutic Interventions

Peptidylarginine Deiminases as Mediators of Microvesicular Release - Novel Therapeutic Interventions

Protein Deimination Signatures in Plasma and Plasma-EVs and Protein Deimination in the Brain Vasculature in a Rat Model of Pre-Motor Parkinson’s Disease

Peptidylarginine Deiminase Isozyme-Specific PAD2, PAD3 and PAD4 Inhibitors Differentially Modulate Extracellular Vesicle Signatures and Cell Invasion in Two Glioblastoma Multiforme Cell Lines

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